Renin inhibitors

ABSTRACT

Disclosed are compounds, pharmaceutical compositions, kits, articles of manufacture, methods of using, and methods of preparing compounds having the formula: 
                         
wherein the variables are as defined herein. The disclosed compounds are inhibitors of Renin.

FIELD OF THE INVENTION

The present invention relates to compounds that may be used to inhibitRenin, as well as compositions of matter and kits comprising thesecompounds. The invention also relates to methods for inhibiting reninand treatment methods using compounds according to the presentinvention.

BACKGROUND OF THE INVENTION

The renin-angiotensin-aldosterone system (“RAAS”) is one of the hormonalmechanisms involved in regulating pressure/volume homeostasis and alsoin the development of hypertension, a condition that can progress tomore serious cardiovascular diseases such as congestive heart failure.Activation of RAAS begins with secretion of the enzyme renin fromjuxtaglomerular cells in the kidney.

Renin, a member of the aspartyl protease family, passes from the kidneysinto the blood where it cleaves angiotensinogen to generate thedecapeptide angiotensin I. Angiotensin I is then cleaved in the lungs,the kidneys and other organs by the angiotensin-converting enzyme (ACE)to form the octapeptide angiotensin II. Angiotensin II, which is knownto work on at least two receptor subtypes (AT₁ and AT₂), increases bloodpressure both directly by arterial vasoconstriction and indirectly byliberating from the adrenal glands the sodium-ion-retaining hormonealdosterone. Angiotensin II also produces other physiological effectssuch as promoting sodium and fluid retention, inhibiting reninsecretion, increasing sympathetic nervous system activity, stimulatingvasopressin secretion, causing a positive cardiac inotropic effect andmodulating other hormonal systems.

Modulation of the RAAS represents a major advance in the treatment ofcardiovascular diseases. In particular, the rationale to develop renininhibitors lies in its specificity (Kleinert H. D., Cardiovasc. Drugs,1995, 9, 645). The only substrate known for renin is angiotensinogen,which can only be processed (under physiological conditions) by Renin.Inhibitors of the enzymatic activity of renin are therefore expected tobring about a reduction in the formation of angiotensin I andangiotensin II.

In view of the foregoing, renin is an especially attractive target forthe discovery of new therapeutics for cardiovascular disease,hypertension, congestive heart failure, myocardial infarction, renalprotection, inflammation, neurological diseases, cancer and otherdiseases. Accordingly, there is a need to find new renin inhibitors foruse as therapeutic agents to treat human diseases. In particular, thereis a continued need for metabolically stable, orally bioavailable renininhibitors that can be prepared on a large scale.

SUMMARY OF THE INVENTION

The present invention relates to compounds that have activity forinhibiting renin and to methods of making these compounds. The presentinvention also provides compositions, articles of manufacture and kitscomprising these compounds.

In one aspect, the invention is directed to a pharmaceutical compositionthat comprises a renin inhibitor according to the present invention asan active ingredient. Pharmaceutical compositions according to theinvention may optionally comprise 0.001%-100% of one or more inhibitorsof this invention. These pharmaceutical compositions may be administeredor coadministered by a wide variety of routes, including for example,orally, parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, or intrathecally. The compositionsmay also be administered or coadministered in slow release dosage forms.

In another aspect, the invention is also directed to kits for treatingdisease states associated with Renin. In one embodiment, the kitcomprises a composition comprising at least one renin inhibitor of thepresent invention in combination with instructions. The instructions mayindicate the disease state for which the composition is to beadministered, storage information, dosing information and/orinstructions regarding how to administer the composition. The kit mayalso comprise packaging materials. The packaging material may comprise acontainer for housing the composition. The kit may also optionallycomprise additional components, such as syringes for administration ofthe composition. The kit may comprise the composition in single ormultiple dose forms.

In another aspect, the invention is related to an article of manufacturethat comprises a composition comprising at least one renin inhibitor ofthe present invention in combination with packaging materials. Thepackaging material may comprise a container for housing the composition.The container may optionally comprise a label indicating the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also optionally compriseadditional components, such as syringes for administration of thecomposition. The kit may comprise the composition in single or multipledose forms.

In still another aspect, the invention is related to methods for usingcompounds, compositions, kits and articles of manufacture.

In one embodiment, the compounds, compositions, kits and articles ofmanufacture are used to inhibit Renin.

In another embodiment, the compounds, compositions, kits and articles ofmanufacture are used to treat a disease state for which renin possessactivity that contributes to the pathology and/or symptomology of thedisease state.

In another embodiment, a compound is administered to a subject whereinrenin activity within the subject is altered, preferably reduced.

In another embodiment, a prodrug of a compound is administered to asubject that is converted to the compound in vivo where it inhibitsRenin.

In another embodiment, a method of inhibiting renin is provided thatcomprises contacting a renin with a compound according to the presentinvention.

In another embodiment, a method of inhibiting renin is provided thatcomprises causing a compound according to the present invention to bepresent in a subject in order to inhibit renin in vivo.

In another embodiment, a method of inhibiting a renin is provided thatcomprises administering a first compound to a subject that is convertedin vivo to a second compound wherein the second compound inhibits reninin vivo. It is noted that the compounds of the present invention may bethe first or second compounds.

In another embodiment, a therapeutic method is provided that comprisesadministering a compound according to the present invention.

In another embodiment, a method of treating a condition in a patientthat is known to be mediated by Renin, or which is known to be treatedby renin inhibitors, comprising administering to the patient atherapeutically effective amount of a compound according to the presentinvention.

In another embodiment, a method is provided for treating a disease statefor which renin possess activity that contributes to the pathologyand/or symptomology of the disease state, the method comprising: causinga compound according to the present invention to be present in a subjectin a therapeutically effective amount for the disease state.

In another embodiment, a method is provided for treating a disease statefor which renin possess activity that contributes to the pathologyand/or symptomology of the disease state, the method comprising:administering a first compound to a subject that is converted in vivo toa second compound such that the second compound is present in thesubject in a therapeutically effective amount for the disease state. Itis noted that the compounds of the present invention may be the first orsecond compounds.

In another embodiment, a method is provided for treating a disease statefor which renin possess activity that contributes to the pathologyand/or symptomology of the disease state, the method comprising:administering a compound according to the present invention to a subjectsuch that the compound is present in the subject in a therapeuticallyeffective amount for the disease state.

In another embodiment, a method is provided for using a compoundaccording to the present invention in order to manufacture a medicamentfor use in the treatment of a disease state that is known to be mediatedby Renin, or that is known to be treated by renin inhibitors.

In a further aspect, the invention is related to methods for preparingcompounds, compositions and kits according to the present invention. Forexample, several synthetic schemes are provided herein for synthesizingcompounds according to the present invention. The invention furtherprovides reagents that are useful in the preparation of the compounds.

It is noted in regard to all of the above embodiments that the presentinvention is intended to encompass all pharmaceutically acceptableionized forms (e.g., salts) and solvates (e.g., hydrates) of thecompounds, regardless of whether such ionized forms and solvates arespecified since it is well know in the art to administer pharmaceuticalagents in an ionized or solvated form. It is also noted that unless aparticular stereochemistry is specified, recitation of a compound isintended to encompass all possible stereoisomers (e.g., enantiomers ordiastereomers depending on the number of chiral centers), independent ofwhether the compound is present as an individual isomer or a mixture ofisomers. Further, unless otherwise specified, recitation of a compoundis intended to encompass all possible resonance forms and tautomers.With regard to the claims, the language “compound having the formula”and “compound of the formula” is intended to encompass the compound andall pharmaceutically acceptable ionized forms and solvates, all possiblestereoisomers, and all possible resonance forms and tautomers unlessotherwise specifically specified in the particular claim.

It is further noted that prodrugs may also be administered which arealtered in vivo and become a compound according to the presentinvention. The various methods of using the compounds of the presentinvention are intended, regardless of whether prodrug delivery isspecified, to encompass the administration of a prodrug that isconverted in vivo to a compound according to the present invention. Itis also noted that certain compounds of the present invention may bealtered in vivo prior to inhibit renin and thus may themselves beprodrugs for another compound. Such prodrugs of another compound may ormay not themselves independently have renin inhibitory activity.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates SEQ ID NO: 1 and 2 referred to in this application.

DEFINITIONS

Unless otherwise stated, the following terms used in the specificationand claims shall have the following meanings for the purposes of thisApplication.

“Alicyclic” means a moiety comprising a non-aromatic ring structure.Alicyclic moieties may be saturated or partially unsaturated with one,two or more double or triple bonds. Alicyclic moieties may alsooptionally comprise heteroatoms such as nitrogen, oxygen and sulfur. Thenitrogen atoms can be optionally quaternerized or oxidized and thesulfur atoms can be optionally oxidized. Examples of alicyclic moietiesinclude, but are not limited to moieties with C₃₋₈ rings such ascyclopropane, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene,cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene,cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.

“Aliphatic” means a moiety characterized by a straight or branched chainarrangement of constituent carbon atoms and may be saturated orpartially unsaturated with one, two or more double or triple bonds.

“Alkoxy” means an oxygen moiety having a further alkyl substituent. Thealkoxy groups of the present invention can be optionally substituted.

“Alkyl” represented by itself means a straight or branched, saturated orunsaturated, aliphatic radical having a chain of carbon atoms,optionally with oxygen (See “oxaalkyl”) or nitrogen atoms (See“azaalkyl”) between the carbon atoms. C_(X) alkyl and C_(X-Y) alkyl aretypically used where X and Y indicate the number of carbon atoms in thechain. For example, C₁₋₆ alkyl includes alkyls that have a chain ofbetween 1 and 6 carbons (e.g., methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, allyl,1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl,ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented alongwith another radical (e.g., as in arylalkyl, heteroarylalkyl) means astraight or branched, saturated or unsaturated aliphatic divalentradical having the number of atoms indicated or when no atoms areindicated means a bond (e.g., (C₆₋₁₀)aryl(C₁₋₃)alkyl includes, benzyl,phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl,2-pyridinylmethyl and the like).

“Alkenyl” means a straight or branched, carbon chain that contains atleast one carbon-carbon double bond. Examples of alkenyl include vinyl,allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, and the like.

“Alkynyl” means a straight or branched, carbon chain that contains atleast one carbon-carbon triple bond. Examples of alkynyl includeethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.

“Alkylene”, unless indicated otherwise, means a straight or branched,saturated or unsaturated, aliphatic, divalent radical. C_(X) alkyleneand C_(X-Y) alkylene are typically used where X and Y indicate thenumber of carbon atoms in the chain. For example, C₁₋₆ alkylene includesmethylene (—CH₂—), ethylene (—CH₂CH₂—), trimethylene (—CH₂CH₂CH₂—),tetramethylene (—CH₂CH₂CH₂CH₂—) 2-butenylene (—CH₂CH═CHCH₂—),2-methyltetramethylene (—CH₂CH(CH₃)CH₂CH₂—), pentamethylene(—CH₂CH₂CH₂CH₂CH₂—) and the like.

“Alkenylene” means a straight or branched, divalent carbon chain havingone or more carbon-carbon double bonds. Examples of alkenylene includeethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl, and the like.

“Alkynylene” means a straight or branched, divalent carbon chain havingone or more carbon-carbon triple bonds. Examples of alkynylene includeethyne-1,2-diyl, propyne-1,3-diyl, and the like.

“Alkylidene” means a straight or branched saturated or unsaturated,aliphatic radical connected to the parent molecule by a double bond.C_(X) alkylidene and C_(X-Y) alkylidene are typically used where X and Yindicate the number of carbon atoms in the chain. For example, C₁₋₆alkylidene includes methylene (═CH₂), ethylidene (═CHCH₃),isopropylidene (═C(CH₃)₂), propylidene (═CHCH₂CH₃), allylidene(═CH—CH═CH₂), and the like).

“Amino” means the radical —NR_(a)R_(b), where R_(a) and R_(b) are eachindependently hydrogen or a non-hydrogen substituent. Representativeamino groups include, without limits, —NH₂, —NHCH₃, —N(CH₃)₂,—NHC₁₋₁₀-alkyl, —N(C₁₋₁₀-alkyl)₂, —NHaryl, —NHheteroaryl, —N(aryl)₂,—N(heteroaryl)₂, and the like. Optionally, R_(a) and R_(b) together withthe nitrogen may also form a ring. Unless indicated otherwise, thecompounds of the invention containing amino moieties may includeprotected derivatives thereof. Suitable protecting groups for aminomoieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and thelike.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals(e.g., birds, and the like).

“Aromatic” means a moiety wherein the constituent atoms make up anunsaturated ring system, all atoms in the ring system are sp² hybridizedand the total number of pi electrons is equal to 4n+2. An aromatic ringmay be such that the ring atoms are only carbon atoms or may includecarbon and non-carbon atoms (see Heteroaryl).

“Aryl” means a monocyclic or polycyclic ring assembly where all the ringatoms are carbon atoms, and at least one of the rings comprising thering assembly is an aromatic ring. If one or more ring atoms is notcarbon (e.g., N, S), the aryl is a heteroaryl. C_(X) aryl and C_(X-Y)aryl are typically used where X and Y indicate the number of carbonatoms in the ring.

“Azaalkyl” means an alkyl, as defined above, except where one or moresubstituted or unsubstituted nitrogen atoms (—N—) are positioned betweencarbon atoms of the alkyl. For example, an (C₂₋₆) azaalkyl refers to achain comprising between 2 and 6 carbons and one or more nitrogen atomspositioned between the carbon atoms.

“Bicyclic” means a two-ringed ring assembly where the two rings arefused together, linked by a single bond or linked by two bridging atoms.

“Bicycloalkyl” means a saturated or partially unsaturated fused bicyclicor bridged polycyclic ring assembly.

“Bicycloaryl” means a ring assembly of two rings, wherein the rings arelinked by a single bond or fused and at least one of the ringscomprising the ring assembly is an aromatic ring. C_(X) bicycloaryl andC_(X-Y) bicycloaryl are typically used where X and Y indicate the numberof carbon atoms in the bicyclic ring assembly and directly attached tothe ring.

“Bridging ring” as used herein refers to a ring that is bonded toanother ring to form a compound having a bicyclic structure where tworing atoms that are common to both rings are not directly bound to eachother. Non-exclusive examples of common compounds having a bridging ringinclude borneol, norbornane, 7-oxabicyclo[2.2.1]heptane, and the like.One or both rings of the bicyclic system may also comprise heteroatoms.

“Carbamoyl” means the radical —OC(O)NR_(a)R_(b) where R_(a) and R_(b)are each independently two further substituents where a hydrogen orcarbon atom is attached to the nitrogen.

“Carbocycle” refers to a ring where all the ring atoms are carbon atoms.

“Carbocyclic ketone derivative” means a carbocyclic derivative whereinthe ring contains a —C(═O)— moiety.

“Carbonyl” typically means a divalent radical —C(═O)—. It is noted thatthe term “carbonyl” when referring to a monovalent substituent canalternatively refer to a substituted carbonyl or acyl group,—C(═O)R_(a), where R_(a) is hydrogen or a non-hydrogen substituent onthe carbonyl carbon, forming different carbonyl-containing groupsincluding acids, acid halides, aldehydes, amides, esters, and ketones.

“Carboxy” typically means a divalent radical —C(O)O—. It is noted thatthe term “carboxy” when referring to a monovalent substituent means asubstituted carboxy, —C(O)OR_(a), where R_(a) is hydrogen or anon-hydrogen substituent on the carboxyl group forming different carboxycontaining groups including acids and esters. It is further noted thatcompounds of the invention containing carboxy moieties may includeprotected derivatives thereof, i.e., where the oxygen is substitutedwith a protecting group. Suitable protecting groups for carboxy moietiesinclude benzyl, tert-butyl, and the like.

“Cyano” means the radical —CN.

“Cycloalkyl” means a radical comprising a non-aromatic, saturated orpartially unsaturated, monocyclic, fused or bridged polycyclic ringassembly. C_(X) cycloalkyl and C_(X-Y) cycloalkyl are typically usedwhere X and Y indicate the number of carbon atoms in the ring assembly.For example, C₃₋₁₀ cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, 2,5-cyclohexadienyl,bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl, oxocyclohexyl,dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-1-yl, and thelike.

“Cycloalkylene” means a divalent radical comprising a saturated orpartially unsaturated, monocyclic or polycyclic ring assembly. C_(X)cycloalkylene and C_(X-Y) cycloalkylene are typically used where X and Yindicate the number of carbon atoms in the ring assembly.

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition that may be caused by,or incident to, medical or veterinary therapy applied to that animal,i.e., the “side effects” of such therapy.

“Fused ring” as used herein refers to a multi-ring assembly wherein therings comprising the ring assembly are so linked that the ring atomsthat are common to two rings are directly bound to each other. The fusedring assemblies may be saturated, partially saturated, carbocyclics,heterocyclics, aromatics, heteroaromatics, and the like. Non-exclusiveexamples of common fused rings include decalin, naphthalene, anthracene,phenanthrene, indole, benzofuran, purine, quinoline, and the like.

“Halo” means fluoro, chloro, bromo or iodo.

“Halo-substituted alkyl”, as an isolated group or part of a largergroup, means “alkyl” substituted by one or more “halo” atoms, as suchterms are defined in this Application. Halo-substituted alkyl includeshaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like (e.g.,halo-substituted (C₁₋₃)alkyl includes chloromethyl, dichloromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl,2,2,2-trifluoro-1,1-dichloroethyl, and the like).

“Heteroalkyl” means alkyl, as defined in this Application, provided thatone or more of the atoms within the alkyl chain is a heteroatom.

“Heteroaryl” means a monocyclic or polycyclic ring assembly wherein atleast one ring atom is a heteroatom and the remaining ring atoms arecarbon, and at least one of the rings comprising the ring assembly is anaromatic ring. Monocyclic heteroaryl groups include, but are not limitedto, cyclic aromatic groups having five or six ring atoms, wherein atleast one ring atom is a heteroatom and the remaining ring atoms arecarbon. The nitrogen atoms of such heteroaryl rings can be optionallyquaternerized and the sulfur atoms of such heteroaryl rings can beoptionally oxidized. Heteroaryl groups of this invention include, butare not limited to, those derived from furan, imidazole, isothiazole,isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrroline, thiazole,1,3,4-thiadiazole, triazole and tetrazole. “Heteroaryl” also includespolycyclic ring assemblies, wherein a heteroaromatic ring is fused orlinked by a bond to one or more rings independently selected from thegroup consisting of an aromatic ring, a cycloalkyl ring, a cycloalkenylring, a heterocycloalkyl ring and another heteroaromatic ring. Bicyclicor tricyclic heteroaryls include, but are not limited to, those derivedfrom benzo[b]furan, benzo[b]thiophene, benzimidazole,imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine,thieno[3,2-b]pyridine, thieno[2,3-b]pyridine, indolizine,imidazo[1,2a]pyridine, quinoline, isoquinoline, phthalazine,quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole,indoline, benzoxazole, benzopyrazole, benzothiazole,imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine,imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine,imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine,pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine,pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine,pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine,pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine,pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine,pyrrolo[1,2-a]pyrazine, triazo[1,5-a]pyridine, pteridine, purine,carbazole, acridine, phenazine, phenothiazene, phenoxazine,1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, pyrido[1,2-a]indole and2(1H)-pyridinone. The polycyclic heteroaryl ring assembly can beattached to the parent molecule through either the heteroaryl groupitself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl groupto which it is fused. The heteroaryl groups of this invention can besubstituted or unsubstituted.

“Heterobicycloaryl” means bicycloaryl, as defined in this Application,provided that one or more of the atoms within the ring assembly is aheteroatom. For example, hetero(C₄₋₁₂)bicycloaryl as used in thisApplication includes, but is not limited to, indoline,2-amino-4-oxo-3,4-dihydropteridin-6-yl, tetrahydroisoquinolinyl, and thelike.

“Heterocycloalkyl” means cycloalkyl, as defined in this Application,provided that one or more of the atoms forming the ring is a heteroatom.Non-exclusive examples of heterocycloalkyl include piperidyl,4-morpholyl, 4-piperazinyl, pyrrolidinyl, perhydropyrrolizinyl,1,3-dioxanyl, 1,4-dioxanyl and the like.

“Heteroatom” refers to an atom that is not a carbon atom. Particularexamples of heteroatoms include, but are not limited to nitrogen,oxygen, and sulfur.

“Heteroatom moiety” includes a moiety where the atom by which the moietyis attached is not a carbon. Examples of heteroatom moieties include—N═, —NR_(c)—, —N⁺(O⁻)═, —O—, —S— or —S(O)₂—, wherein R_(c) is a furthersubstituent.

“Heterobicycloalkyl” means bicycloalkyl, as defined in this Application,provided that one or more of the atoms within the ring is a heteroatom.For example hetero(C₉₋₁₂)bicycloalkyl as used in this applicationincludes, but is not limited to, 3-aza-bicyclo[4.1.0]hept-3-yl,2-aza-bicyclo[3.1.0]hex-2-yl, 3-aza-bicyclo[3.1.0]hex-3-yl, and thelike.

“Heterocycle” refers to a ring moiety, saturated, unsaturated oraromatic, where at least one ring atom is a heteroatom and the remainingring atoms are carbon.

“Heterocycloalkylene” means cycloalkylene, as defined in thisApplication, provided that one or more of the ring member carbon atomsis replaced by a heteroatom.

“Hydroxy” means the radical —OH.

“IC₅₀” refers to the molar concentration of an inhibitor that produces50% inhibition of the target enzyme.

“Iminoketone derivative” means a derivative comprising the moiety—C(NR)—, wherein R comprises a hydrogen or carbon atom attached to thenitrogen.

“Isomers” mean any compounds having identical molecular formulae butdiffering in the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers.”Stereoisomers that are not mirror images of one another are termed“diastereomers” and stereoisomers that are nonsuperimposable mirrorimages are termed “enantiomers” or sometimes “optical isomers.” A carbonatom bonded to four different substituents (where no two are the same)is termed a “chiral center.” A compound with one chiral center has twoenantiomeric forms of opposite chirality. A mixture of equal amounts ofthe two enantiomeric forms is termed a “racemic mixture.” A compoundthat has more than one chiral center has 2^(n-1) enantiomeric pairs,where n is the number of chiral centers. Compounds with more than onechiral center may exist as ether an individual diastereomer or as amixture of diastereomers, termed a “diastereomeric mixture.” When onechiral center is present a stereoisomer may be characterized by theabsolute configuration of that chiral center. Absolute configurationrefers to the arrangement in space of the substituents attached to thechiral center. Enantiomers are characterized by the absoluteconfiguration of their chiral centers and described by the R- andS-sequencing rules of Cahn, Ingold and Prelog. Conventions forstereochemical nomenclature, methods for the determination ofstereochemistry and the separation of stereoisomers are well known inthe art (e.g., see “Advanced Organic Chemistry”, 4th edition, March,Jerry, John Wiley & Sons, New York, 1992).

“Linker” means a series of atoms sequentially connected by chemicalbonds and in a continuous linking relation which extends between twoattachment points. A linker may be linear, cyclic or a combination oflinear portions and cyclic portions.

The length of the linker or “the number of atoms as measured between thetwo defined attachment points” refers only to the atoms that are in thesequential linking relation; atoms that are attached to one linker atom,but are not in this continuous linking relationship with another linkeratoms (e.g., a substituent on one of the linker atom) are not countedtowards the length of the linker.

The method of counting atoms is the same for linker groups that compriseonly a linear portion and for linker groups that comprise substituentsextending from a chain of atoms to form cyclic groups: only the atomssequentially linking the attachment points defined for L are countedtoward the atom number, not the substituents. Further, only ring atomson the shorter side of the ring that are in continuous sequentiallinking relationship with the rest of the linker group are counted. Forexample, in the following example of a Linker L

where a substituent from each of linker atoms 1 and 3 are taken togetherto form the five-membered ring, the number of atoms constituting thelength of this Linker L is 5, which includes the three ring atoms (atoms1, 2, and 3) on the shorter side of the 5-membered heterocyclic ring andthe two atoms (atoms 4 and 5) on the linear portion of the linker.

“Moiety” means an interconnected group of atoms, generally referred toby its most characteristic structural component. For example, a“carbonyl moiety” refers to groups that contain a carbonyl group.

“Nitro” means the radical —NO₂.

“Oxaalkyl” means an alkyl, as defined above, except where one or moreoxygen atoms (—O—) are positioned between carbon atoms of the alkyl. Forexample, an (C₂₋₆)oxaalkyl refers to a chain comprising between 2 and 6carbons wherein one or more oxygen atoms is positioned between twocarbon atoms.

“Oxy” typically means the radical —O—. It is noted that the term “oxy”when referring to a monovalent radical can alternatively refer to asubstituents oxy group, —OR—, where R is hydrogen or a non-hydrogensubstituent on the oxy radical forming oxy-containing groups includinghydroxy, alkoxy, aryloxy, heteroaryloxy and carbonyloxy.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of compounds of thepresent invention which are pharmaceutically acceptable, as definedabove, and which possess the desired pharmacological activity. Suchsalts include acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or with organic acids such as aceticacid, propionic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, p-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonicacid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

“Prodrug” means a compound that is convertible in vivo metabolicallyinto an inhibitor according to the present invention. The prodrug itselfmay or may not also have renin inhibitory activity. For example, aninhibitor comprising a hydroxy group may be administered as an esterthat is converted by hydrolysis in vivo to the hydroxy compound.Suitable esters that may be converted in vivo into hydroxy compoundsinclude acetates, citrates, lactates, tartrates, malonates, oxalates,salicylates, propionates, succinates, fumarates, maleates,methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,di-p-toluoyltartrates, methanesulfonates, ethanesulfonates,benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates, quinates,esters of amino acids, and the like. Similarly, an inhibitor comprisingan amine group may be administered as an amide or as an N-alkyl(particularly N-methyl or N-ethyl) that is converted by hydrolysis oroxidation in vivo to the amine compound.

“Protected derivatives” means derivatives of inhibitors in which areactive site or sites are blocked with protecting groups. Protectedderivatives are useful in the preparation of inhibitors or in themselvesmay be active as inhibitors. Examples of protected group includes, butare not limited to, acetyl, tetrahydropyran, methoxymethyl ether,β-methoxyethoxymethyl ether, p-methoxybenzyl, methylthiomethyl ether,pivaloyl, silyl ether, carbobenzyloxy, benzyl, tert-butoxycarbonyl,p-methoxyphenyl, 9-fluorenylmethyloxycarbonyl, acetals, ketals, acylals,dithianes, methylesters, benzyl esters, tert-butyl esters, and silylesters. A comprehensive list of suitable protecting groups can be foundin T. W. Greene, Protecting Groups in Organic Synthesis, 3rd edition,John Wiley & Sons, Inc. 1999.

“Ring” means a carbocyclic or a heterocyclic system.

“Substituent convertible to hydrogen in vivo” means any group that isconvertible to a hydrogen atom by enzymological or chemical meansincluding, but not limited to, hydrolysis, reduction and oxidation.Examples include hydrolyzable groups, such as acyl groups, groups havingan oxycarbonyl group, amino acid residues, peptide residues,o-nitrophenylsulfenyl, trimethylsilyl, tetrahydro-pyranyl,diphenylphosphinyl, and the like. Examples of acyl groups includeformyl, acetyl, trifluoroacetyl, and the like. Examples of groups havingan oxycarbonyl group include ethoxycarbonyl, t-butoxycarbonyl[(—O)CO—C(CH₃)₃], benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,vinyloxycarbonyl, β-(p-toluenesulfonyl)ethoxycarbonyl, and the like.Examples of suitable amino acid residues include amino acid residues perse and amino acid residues that are protected with a protecting group.Suitable amino acid residues include, but are not limited to, residuesof Gly (glycine), Ala (alanine; —C(O)CH(NH2)CH₃), Arg (arginine), Asn(asparagine), Asp (aspartic acid), Cys (cysteine), Glu (glutamic acid),His (histidine), Ile (isoleucine), Leu (leucine; —C(O)CH(NH₂)CH₂CH(CH₃)₂Lys (lysine), Met (methionine), Phe (phenylalanine), Pro (proline), Ser(serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val(valine), Nva (norvaline), Hse (homoserine), 4-Hyp (4-hydroxyproline),5-Hyl (5-hydroxylysine), Orn (ornithine) and β-Ala. Examples of suitableprotecting groups include those typically employed in peptide synthesis,including acyl groups (such as formyl and acetyl), arylmethyloxycarbonylgroups (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl),t-butoxycarbonyl groups [—(O)CO—C(CH₃)₃], and the like. Suitable peptideresidues include peptide residues comprising two to five, and optionallytwo to three, of the aforesaid amino acid residues. Examples of suchpeptide residues include, but are not limited to, residues of suchpeptides as Ala-Ala [—C(O)CH(NH)CH₃—C(O)CH(NH₂)CH₃)], Gly-Phe, Nva-Nva,Ala-Phe, Gly-Gly, Gly-Gly-Gly, Ala-Met, Met-Met, Leu-Met and Ala-Leu.The residues of these amino acids or peptides can be present instereochemical configurations of the D-form, the L-form or mixturesthereof. In addition, the amino acid or peptide residue may have anasymmetric carbon atom. Examples of suitable amino acid residues havingan asymmetric carbon atom include residues of Ala, Leu, Phe, Trp, Nva,Val, Met, Ser, Lys, Thr and Tyr. Peptide residues having an asymmetriccarbon atom include peptide residues having one or more constituentamino acid residues having an asymmetric carbon atom. Examples ofsuitable amino acid protecting groups include those typically employedin peptide synthesis, including acyl groups (such as formyl and acetyl),arylmethyloxycarbonyl groups (such as benzyloxycarbonyl andp-nitrobenzyloxycarbonyl), t-butoxycarbonyl groups [—(O)CO—C(CH₃)₃], andthe like. Other examples of substituents “convertible to hydrogen invivo” include reductively eliminable hydrogenolyzable groups. Examplesof suitable reductively eliminable hydrogenolyzable groups include, butare not limited to, arylsulfonyl groups (such as o-toluenesulfonyl);methyl groups substituted with phenyl or benzyloxy (such as benzyl,trityl and benzyloxymethyl); arylmethoxycarbonyl groups (such asbenzyloxycarbonyl and o-methoxy-benzyloxycarbonyl); andhalogenoethoxycarbonyl groups (such as β,β,β-trichloroethoxycarbonyl andβ-iodoethoxycarbonyl). Further examples of substituents “convertible tohydrogen in vivo” include enzymatic oxidizable groups such as N-alkyls,particularly N-methyl and N-ethyl.

“Substituted or unsubstituted” or “optionally substituted” means that agiven moiety may consist of only hydrogen atoms bound at availablevalences (unsubstituted) or may further comprise one or morenon-hydrogen atoms bound through available valencies (substituted). Thesubstituents of an “optionally substituted” group may include, withoutlimitation one or more substituents independently selected from thegroup or designated subsets thereof, aldehyde, (C₁₋₁₀)alkyl, alkylene,alkylidene, amide, amino, aminoalkyl, aryl, bicycloalkyl, bicycloaryl,carbamoyl, carbocyclyl, carboxyl, carbonyl group, cycloalkyl,cycloalkylene, ester, halo, heterobicycloalkyl, heterocycloalkylene,heteroaryl, heterobicycloaryl, heterocycloalkyl, oxo, hydroxy,iminoketone, ketone, nitro, oxaalkyl, and oxoalkyl moieties, each ofwhich may optionally also be substituted or unsubstituted.

In one particular embodiment, examples of substituents include, but arenot limited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₄)aryloxy, hetero(C₁₋₁₃)aryloxy,carbonyl, oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl. In addition, the substituent is itselfoptionally substituted by a further substituent. In one particularembodiment, examples of the further substituent include, but are notlimited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl.

“Sulfinyl” means the radical —S(O)—. It is noted that the term“sulfinyl” when referring to a monovalent substituent can alternativelyrefer to a substituted sulfinyl group, —S(═O)R, where R is hydrogen or anon-hydrogen substituent on the sulfur atom forming different sulfinylgroups including sulfinic acids, sulfinamides, sulfinyl esters, andsulfoxides.

“Sulfonyl” means the radical —S(O)₂—. It is noted that the term“sulfonyl” when referring to a monovalent substituent can alternativelyrefer to a substituted sulfonyl group, —S(═O)₂R, where R is hydrogen ora non-hydrogen substituent on the sulfur atom forming different sulfonylgroups including sulfonic acids, sulfonamides, sulfonate esters, andsulfones.

“Therapeutically effective amount” means that amount which, whenadministered to an animal for treating a disease, is sufficient toeffect such treatment for the disease.

“Thiocarbonyl” means the radical —C(S)—. It is noted that the term“thiocarbonyl” when referring to a monovalent substituent canalternatively refer to a substituted thiocarbonyl group, —C(═S)₂R, whereR is hydrogen or a non-hydrogen substituent on the carbon atom formingdifferent thiocarbonyl groups including thioacids, thioamides,thioesters, and thioketones.

“Treatment” or “treating” means any administration of a compound of thepresent invention and includes:

-   -   (1) preventing the disease from occurring in an animal which may        be predisposed to the disease but does not yet experience or        display the pathology or symptomatology of the disease,    -   (2) inhibiting the disease in an animal that is experiencing or        displaying the pathology or symptomatology of the diseased        (i.e., arresting further development of the pathology and/or        symptomatology), or    -   (3) ameliorating the disease in an animal that is experiencing        or displaying the pathology or symptomatology of the diseased        (i.e., reversing the pathology and/or symptomatology).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds, compositions, kits andarticles of manufacture that may be used to inhibit Renin. The presentinvention also relates to methods for inhibiting renin and treatmentmethods using compounds according to the present invention. The presentinvention further relates to method of making the inhibitors of theinvention and compounds that are useful in the preparation of theinhibitors of the invention.

It is noted that the compounds of the present invention may also possessinhibitory activity for other aspartyl proteases (e.g., pepsin,gastricsin, napsin, BACE 1 & 2 and cathepsin D and E) and thus may beused to address disease states associated with these other familymembers. In addition, the compounds of the present invention may beuseful as inhibitors of plasmepsins to treat malaria and as inhibitorsof Candida albicans secreted aspartyl proteases to treat fungalinfections.

In the first aspect, the invention relates to renin inhibiting compoundsand their polymorphs, solvates, esters, tautomers, enantiomers,pharmaceutical acceptable salts, and prodrugs.

In one embodiment, compounds of the present invention is of the formula:

wherein

-   -   N^(a) denotes a nitrogen atom;    -   L is a linker moiety between 1-5 atoms in length as measured        between Q and N^(a);    -   Q is selected from the group consisting of —C(═O)—, —C(═S)—, and        —C(═NR₁₂)—;    -   R₁ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicyoloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₂₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,        amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicyoloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₃ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicyoloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₇ is selected from the group consisting of hydrogen,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        carboxamidoalkyl, amidoalkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ and a substituent of L are        taken together to form a ring; and    -   R₁₂ is selected from the group consisting of hydrogen, hydroxyl,        alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, each        substituted or unsubstituted;    -   provided that R₁ and R₃ are not both hydrogen;

wherein

-   -   the compound includes any hydrate, solvate, ester, tautomer,        enantiomer, and pharmaceutically acceptable salt form of the        compound.

In another embodiment, compounds of the present invention is of theformula:

wherein

-   -   C^(a) denotes a carbon atom;    -   N^(a) denotes a nitrogen atom;    -   L is a linker moiety between 1-5 atoms in length as measured        between C^(a) and N^(a);    -   R₁ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₂₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,        amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₃ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₇ is selected from the group consisting of hydrogen,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, carboxamido        alkyl, amido alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cyclo alkyl, hetero        (C₂₋₁₂)cyclo alkyl, (C₉₋₁₂)bicyclo alkyl, hetero (C₃₋₁₂)bicyclo        alkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, or        R₇ and a substituent of L are taken together to form a ring;    -   provided that R₁ and R₃ are not both hydrogen;

wherein

-   -   the compound includes any hydrate, solvate, ester, tautomer,        enantiomer, and pharmaceutically acceptable salt form of the        compound.

In another embodiment, compounds of the present invention is of theformula:

wherein

-   -   C^(a) denotes a carbon atom;    -   N^(a) denotes a nitrogen atom;    -   L is a linker moiety between 1-5 atoms in length as measured        between C^(a) and N^(a), wherein the first atom of L attaching        to C^(a) is a nitrogen atom;    -   R₁ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₂₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,        amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₃ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₇ is selected from the group consisting of hydrogen,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        carboxamidoalkyl, amidoalkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ and a substituent of L are        taken together to form a ring; and    -   R₁₂ is selected from the group consisting of hydrogen, hydroxyl,        alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, each        substituted or unsubstituted;    -   provided that R₁ and R₃ are not both hydrogen;

wherein

-   -   the compound includes any hydrate, solvate, ester, tautomer,        enantiomer, and pharmaceutically acceptable salt form of the        compound.

In another embodiment, compounds of the present invention is of theformula

wherein

-   -   C^(a) denotes a carbon atom;    -   N^(a) denotes a nitrogen atom;    -   L is a linker moiety between 1-5 atoms in length as measured        between C^(a) and N^(a), wherein the first atom of L attaching        to C^(a) is a nitrogen atom;    -   R₁ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₂₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,        amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₃ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₇ is selected from the group consisting of hydrogen,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        carboxamidoalkyl, amidoalkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ and a substituent of L are        taken together to form a ring;    -   provided that R₁ and R₃ are not both hydrogen;

wherein

-   -   the compound includes any hydrate, solvate, ester, tautomer,        enantiomer, and pharmaceutically acceptable salt form of the        compound.

In one variation of any one of the preceding embodiments, L is a linkermoiety between 1-4 atoms in length as measured between Q and N^(a) orbetween C^(a) and N^(a).

In another variation, L is a linker moiety between 2-4 atoms in lengthas measured between Q and N^(a) or between C^(a) and N^(a).

In another variation, L is a linker moiety between 3-4 atoms in lengthas measured between Q and N^(a) or between C^(a) and N^(a).

In another variation, one or more of the atoms of L that provide the 1-5atom length as measured between Q and N^(a) or between C^(a) and N^(a)form a portion of a substituted or unsubstituted three, four, five, six,or seven membered ring.

In another variation, one or more of the atoms of L that provide the 1-5atom length as measured between Q and N^(a) or between C^(a) and N^(a)form a portion of a substituted or unsubstituted three, four, five, six,or seven membered cycloalkyl and heterocycloalkyl ring.

In another variation, one or more of the atoms of L that provide the 1-5atom length as measured between Q and N^(a) or between C^(a) and N^(a)form a portion of a substituted or unsubstituted three, four, five, six,seven, eight or nine membered alicyclic and heteroalicyclic ring.

In another variation, one or more of the atoms of L that provide the 1-5atom length as measured between Q and N^(a) or between C^(a) and N^(a)form a portion of a substituted or unsubstituted three, four, five, six,seven, eight or nine membered aromatic ring.

In another variation, one or more of the atoms of L that provide the 1-5atom length as measured between Q and N^(a) or between C^(a) and N^(a)form a portion of a ring selected from the group consisting ofcyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene,cyclohexane, cyclohexene, cyclohexadiene, benzene, cycloheptane,cycloheptene, and cycloheptadiene, cyclooctane, cyclooctene, andcyclooctadiene, each substituted or unsubstituted.

In another variation, one or more of the atoms of L that provide the 1-5atom length as measured between Q and N^(a) or between C^(a) and N^(a)form a portion of a ring selected from the group consisting of benzene,biphenyl, pyran, pyridine, piperidine, dioxane, morpholine, dithiane,thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, andtriazine, each substituted or unsubstituted.

In another variation, one or more of the atoms of L that provide the 1-5atom length as measured between Q and N^(a) or between C^(a) and N^(a)form a portion of a moiety selected from the group consisting of furan,thiofuran, pyrrole, isopyrrole, pyrazole, isoimidazole, triazole,isoxazole, oxazole, thiazole, isothiazole, oxadiazole, oxatriazole,pyridine, pyridazine, pyrimidine, pyrazine, triazine, benzofuran,isobenzofuran, benzothiofuran, isobenzothiofuran, indole, isobenzazole,quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, andpyridopyridine, each substituted or unsubstituted.

In another variation, the atoms of L in a direct chain between Q andN^(a) or between C^(a) and N^(a) are selected from the group consistingof carbon, oxygen, nitrogen, and sulfur atoms.

In another variation, the atoms of L in a direct chain between Q andN^(a) or between C^(a) and N^(a) are selected from the group consistingof carbon and nitrogen atoms.

In another variation, when Q is —C(O)—, the atoms of L in a direct chainbetween Q and N^(a) or between C^(a) and N^(a) are all carbon atoms.

In another variation, one or more of the atoms of L that provide the 1-5atom length as measured between Q and N^(a) or between C^(a) and N^(a)form a portion of a substituted or unsubstituted piperazine ring.

In another variation, L is -(A)_(k);

-   -   wherein        -   k is selected from the group consisting of 1, 2, 3, 4 and 5;        -   each A is independently selected from the group consisting            of —NR₉—, —O—, —S—, and —CR₅R₆—, where        -   R₅ and R₆ are each independently selected from the group            consisting of hydrogen, oxycarbonyl, sulfonyl, sulfinyl,            (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,            thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,            sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,            hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,            hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,            (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each            substituted or unsubstituted, and R₆ may be absent when the            carbon to which it is bound forms part of a double bond, and            R₅ and R₆ on a given carbon may be taken together to form            ═O, ═S, or ═NR₁₀, wherein R₁₀ is selected from the group            consisting of hydrogen, hydroxyl, alkoxy, aryloxy,            heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₄alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl,            each substituted or unsubstituted;        -   R₉ is selected from the group consisting of hydrogen,            alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl,            halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, aminocarbonylalkyl,            thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,            sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,            alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,            hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,            hetero(C₄₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,            (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each            substituted or unsubstituted, and R₉ may be absent when the            nitrogen to which it is attached forms part of a double            bond; and        -   any two adjacent R₅, R₆, R₇ and R₉ may be taken together to            form a substituted or unsubstituted five, six, seven or            eight membered ring.

In another variation, L is *—NR₉-(A)_(k′)-,

-   -   wherein        -   * indicates the point of attachment of —NR₉-(A)_(k′)- to            either Q or C^(a);        -   k′ is selected from the group consisting of 1, 2, 3 and 4;        -   each A is independently selected from the group consisting            of —NR₉—, —O—, —S—, and —CR₅R₆— where            -   R₅ and R₆ are each independently selected from the group                consisting of hydrogen, oxycarbonyl, sulfonyl, sulfinyl,                (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,                thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,                sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,                imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,                hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,                heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,                hetero (C₄₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cyclo                alkyl, hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,                hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl,                hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and                hetero(C₄₋₁₂)bicycloaryl, each substituted or                unsubstituted, and R₅ and R₆ on a given carbon may be                taken together to form ═O, ═S, or ═NR₁₀, where R₁₀ is                selected from the group consisting of hydrogen,                hydroxyl, alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl,                halo(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,                hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,                heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,                hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, and                hetero(C₂₋₁₀)aryl, each substituted or unsubstituted,                and R₆ is absent when the carbon to which it is bound                forms part of a double bond;        -   R₉ is selected from the group consisting of hydrogen,            alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl,            halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, aminocarbonylalkyl,            thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,            sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,            alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,            hetero(C₄₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,            hetero(C₄₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,            (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each            substituted or unsubstituted, R₉ is absent when the nitrogen            to which it is bound forms part of a double bond; and        -   any two adjacent R₅ and R₆ may be taken together to form a            five, six, seven, or eight membered ring, each substituted            or unsubstituted,        -   R₉ and one of R₅ and R₆ may be taken together to form a            five, six, seven, or eight membered ring, each substituted            or unsubstituted,        -   R₇ and one of R₅ and R₆ may be taken together to form a            five, six, seven, or eight membered ring, each substituted            or unsubstituted, and        -   R₇ and R₉ may be taken together to form a five, six, seven,            or eight membered ring, each substituted or unsubstituted.

In another variation, -L-N^(a)R₇H is selected from the group consistingof

-   -   where        -   k is 0, 1, 2, 3, 4 or 5;        -   n is 0, 1 or 2;        -   p is 0, 1, 2, 3 or 4;        -   each R₄ is independently selected from the group consisting            of hydrogen, oxo, oxyalkyl, alkoxycarbonyl, carbonyl,            thioalkyl, alkoxy, oxycarbonyl, aminocarbonyl, amino, amido,            carboxamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,            halo(C₁₋₁₀)alkyl, oxyalkyl, alkoxyalkyl, alkylthioalkyl,            carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,            sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,            imino(C₁₋₃)alkyl, carboxamido(C₁₋₁₀)alkyl,            amido(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,            (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,            hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,            hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,            (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each            substituted or unsubstituted;        -   R₅ and R₆ are each independently selected from the group            consisting of hydrogen, oxycarbonyl, sulfonyl, sulfinyl,            (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,            thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,            sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,            hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,            hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,            (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each            substituted or unsubstituted, and R₅ and R₆ on a given            carbon may be taken together to form ═O, ═S, or ═NR₁₀, where            R₁₀ is selected from the group consisting of hydrogen,            hydroxyl, alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl,            halo(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl,            each substituted or unsubstituted, and R₆ is absent when the            carbon to which it is bound forms part of a double bond;        -   R₇ is selected from the group consisting of hydrogen,            (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,            carboxamidoalkyl, amidoalkyl, thiocarbonyl(C₁₋₃)alkyl,            sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,            imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,            hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,            hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,            (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each            substituted or unsubstituted, and        -   R₉ is selected from the group consisting of hydrogen,            alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl,            halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, aminocarbonylalkyl,            thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,            sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,            alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,            hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,            hetero(C₄₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,            (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each            substituted or unsubstituted.

In another embodiment, the compound has the formula

wherein

-   -   C_(a) denotes a carbon atom;    -   N_(a) denotes a nitrogen atom;    -   n is 0, 1, or 2;    -   p is 0, 1, 2, 3, or 4; and    -   R₁ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₂₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,        amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₃ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   each R₄ is independently selected from the group consisting of        hydrogen, oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl,        alkoxy, oxycarbonyl, aminocarbonyl, amino, amido, carboxamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl,        alkoxyalkyl, alkylthioalkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        carboxamido(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,        (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   provided that R₁ and R₃ are not both hydrogen;

wherein

-   -   the compound includes any hydrate, solvate, ester, tautomer,        enantiomer, and pharmaceutically acceptable salt form of the        compound.

In another embodiment, the compound has the formula

wherein

-   -   C_(a) denotes a carbon atom;    -   N_(a) denotes a nitrogen atom;    -   p is 0, 1, 2, 3, or 4; and    -   R₁ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₂₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,        amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₃ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   each R₄ is independently selected from the group consisting of        hydrogen, oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl,        alkoxy, oxycarbonyl, aminocarbonyl, amino, amido, carboxamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl,        alkoxyalkyl, alkylthioalkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        carboxamido(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,        (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   provided that R₁ and R₃ are not both hydrogen;

wherein

-   -   the compound includes any hydrate, solvate, ester, tautomer,        enantiomer, and pharmaceutically acceptable salt form of the        compound.

In another embodiment, the compound has the formula

wherein

-   -   C_(a) denotes a carbon atom;    -   N_(a) denotes a nitrogen atom;    -   p is 0, 1, 2, 3, or 4; and    -   R₁ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₂₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,        amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₃ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   each R₄ is independently selected from the group consisting of        hydrogen, oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl,        alkoxy, oxycarbonyl, aminocarbonyl, amino, amido, carboxamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl,        alkoxyalkyl, alkylthioalkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        carboxamido(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,        (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   provided that R₁ and R₃ are not both hydrogen;

wherein

-   -   the compound includes any hydrate, solvate, ester, tautomer,        enantiomer, and pharmaceutically acceptable salt form of the        compound.

In another embodiment, the compound has the formula

wherein:

-   -   C_(a) denotes a carbon atom;    -   N_(a) denotes a nitrogen atom;    -   n is 0, 1, or 2;    -   p is 0, 1, 2, 3, or 4;    -   R₁ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₂₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,        amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₃ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   each R₄ is independently selected from the group consisting of        hydrogen, oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl,        alkoxy, oxycarbonyl, aminocarbonyl, amino, amido, carboxamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl,        alkoxyalkyl, alkylthioalkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        carboxamido(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,        (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₇ is selected from the group consisting of hydrogen,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, carboxamido        alkyl, amido alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl, hetero        (C₂₋₁₂)cyclo alkyl, (C₉₋₁₂)bicyclo alkyl, hetero (C₃₋₁₂)bicyclo        alkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   provided that R₁ and R₃ are not both hydrogen;

wherein

-   -   the compound includes any polymorph, solvate, ester, tautomer,        enantiomer, and pharmaceutically acceptable salt form of the        compound.

In another embodiment, the compound has the formula

wherein:

-   -   C_(a) denotes a carbon atom;    -   N_(a) denotes a nitrogen atom;    -   p is 0, 1, 2, 3, or 4;    -   R₁ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₂₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,        amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₃ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   each R₄ is independently selected from the group consisting of        hydrogen, oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl,        alkoxy, oxycarbonyl, aminocarbonyl, amino, amido, carboxamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl,        alkoxyalkyl, alkylthioalkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        carboxamido(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,        (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₇ is selected from the group consisting of hydrogen,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, carboxamido        alkyl, amido alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cyclo alkyl, hetero        (C₂₋₁₂)cyclo alkyl, (C₉₋₁₂)bicyclo alkyl, hetero (C₃₋₁₂)bicyclo        alkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;    -   provided that R₁ and R₃ are not both hydrogen;

wherein

-   -   the compound includes any polymorph, solvate, ester, tautomer,        enantiomer, and pharmaceutically acceptable salt form of the        compound.

In another embodiment, the compound has the formula:

wherein:

-   -   C_(a) denotes a carbon atom;    -   N_(a) denotes a nitrogen atom;    -   k is 0, 1, 2, 3,4 or 5;    -   R₁ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₂₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,        amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₃ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   each R₄ is independently selected from the group consisting of        hydrogen, oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl,        alkoxy, oxycarbonyl, aminocarbonyl, amino, amido, carboxamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl,        alkoxyalkyl, alkylthioalkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        carboxamido(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,        (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₅ and R₆ are each independently selected from the group        consisting of hydrogen, oxycarbonyl, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, and R₅ and R₆ on a given carbon        may be taken together to form ═O, ═S, or ═NR₁₀, where R₁₀ is        selected from the group consisting of hydrogen, hydroxyl,        alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl,        each substituted or unsubstituted, and R₆ is absent when the        carbon to which it is bound forms part of a double bond;    -   R₇ is selected from the group consisting of hydrogen,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        carboxamidoalkyl, amidoalkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, and    -   R₉ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, aminocarbonylalkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₄₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   provided that R₁ and R₃ are not both hydrogen;

wherein

-   -   the compound includes any hydrate, solvate, ester, tautomer,        enantiomer, and pharmaceutically acceptable salt form of the        compound.

In another embodiment, the compound has the formula:

wherein

-   -   C_(a) denotes a carbon atom;    -   N_(a) denotes a nitrogen atom;    -   n is 0, 1, or 2;    -   p is 0, 1, 2, 3, or 4;    -   R₁ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₂₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,        amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₃ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   each R₄ is independently selected from the group consisting of        hydrogen, oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl,        alkoxy, oxycarbonyl, aminocarbonyl, amino, amido, carboxamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl,        alkoxyalkyl, alkylthioalkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        carboxamido(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,        (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₉ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, aminocarbonylalkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₄₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   provided that R₁ and R₃ are not both hydrogen;

wherein

-   -   the compound includes any hydrate, solvate, ester, tautomer,        enantiomer, and pharmaceutically acceptable salt form of the        compound.

In another embodiment, the compound has the formula

wherein:

-   -   C_(a) denotes a carbon atom;    -   N_(a) denotes a nitrogen atom;    -   p is 0, 1, 2, 3, or 4;    -   R₁ is selected from the group consisting of hydrogen, carbonyl,        oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₂₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,        amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₃ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   each R₄ is independently selected from the group consisting of        hydrogen, oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl,        alkoxy, oxycarbonyl, aminocarbonyl, amino, amido, carboxamido,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl,        alkoxyalkyl, alkylthioalkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        carboxamido(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,        (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₉ is selected from the group consisting of hydrogen, alkoxy,        aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, aminocarbonylalkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₄₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   provided that R₁ and R₃ are not both hydrogen;

wherein

-   -   the compound includes any hydrate, solvate, ester, tautomer,        enantiomer, and pharmaceutically acceptable salt form of the        compound.

In one variation of any one of the preceding embodiments and variations,R₁ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, aryl(C₁₋₁₀)alkyl, andheteroaryl(C₁₋₅)alkyl, each substituted or unsubstituted.

In another variation, R₁ is selected from the group consisting of(C₁₋₁₀)alkyl, (C₃₋₈)cycloalkyl and (C₃₋₈)cycloalkyl(C₁₋₃)alkyl.

In another variation, R₁ comprises an aromatic ring and is selected froma group consisting of phenyl, benzyl, hetero(C₂₋₅)aryl,hetero(C₂₋₅)arylmethyl, each substituted or unsubstituted, where

-   -   the hetero(C₂₋₅)aryl and hetero(C₂₋₅)arylmethyl may contain up        to three heteroatoms as ring atoms, and each of the heteroatoms        is independently selected from the group consisting of nitrogen,        oxygen and sulfur atoms, and    -   the aromatic ring may be unsubstituted or substituted with 1-4        substituents independently selected from the group consisting of        alkyl, halo, and alkoxy, each substituted or unsubstituted.

In another variation, R₁ is selected from the group of consisting of

wherein

-   -   each J is independently selected from the group consisting of        —CR_(8′)— and —N—;    -   each J¹ is independently selected from the group consisting of        —CR₈R_(8′)— and —NR₁₁—; and    -   not more than two ring atoms of R₁ is —N— or —NR₁₁—;        -   where        -   each of R₈ and R_(8′) is independently selected from the            group consisting of hydrogen, halo, alkyl, and alkoxy, each            substituted or unsubstituted, and R_(8′) may be absent when            the carbon to which it is bound forms a double bond, and        -   each R₁₁ is independently selected from the group consisting            of hydrogen, alkyl and alkoxy, each substituted or            unsubstituted, and R₁₁ may be absent when the nitrogen to            which it is bound forms a double bond.

In another variation, R₁ is selected from the group consisting of

wherein

-   -   m is 0, 1, 2, 3 or 4;    -   1 is 0, 1, 2 or 3;    -   each R₁₃ is selected from the group consisting of alkyl, halo,        and alkoxy, each substituted or unsubstituted.

In another variation, R₁ is phenyl or benzyl. In another variation, R₁is phenyl. In another variation, R₁ is benzyl.

In another variation, R₁ is a fluoro or chloro substituted phenyl orbenzyl. In another variation, R₁ is a fluoro or chloro substitutedphenyl. In another variation, R₁ is a fluoro or chloro substitutedbenzyl.

In another variation, R₁ is selected from the group consisting ofisopropyl, cyclopropyl, and cyclopropylmethyl.

In one variation of the above embodiments and variations, R₂ is selectedfrom the group consisting of (C₁₋₁₀)alkyl, (C₁₋₁₀)alkoxy(C₁₋₃)alkyl,carboxamido(C₁₋₃)alkyl, amido(C₁₋₃)alkyl, alkylsulfonyl(C₁₋₃)alkyl,arylsulfonyl(C₁₋₃)alkyl, (C₁₋₁₀)alkylcarbonyl(C₁₋₃)alkyl,halo(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl, eachsubstituted or unsubstituted.

In another variation of the above embodiments and variations, R₂ isselected from the group consisting of unsubstituted or substituted(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, (C₁₋₆)alkoxy(C₁₋₃)alkyl,(C₅₋₈)aryloxyalkoxy, (C₁₋₁₀)alkylcarboxamido(C₁₋₃)alkyl,(C₅₋₈)arylcarboxamido(C₁₋₃)alkyl, amido(C₁₋₃)alkyl,(C₁₋₆)alkylsulfonyl(C₁₋₃)alkyl, (C₅₋₈)arylsulfonyl(C₁₋₃)alkyl,(C₅₋₈)arylsulfonylamino(C₁₋₃)alkyl,(C₁₋₁₀)alkylsulfonylamino(C₁₋₃)alkyl, and(C₁₋₆)alkylcarbonyl(C₁₋₃)alkyl.

In another variation, R₂ is selected from a group, the members of whichcomprise a three, four, five, six or seven membered ring, and said groupconsists of (C₃₋₇)cycloalkyl, hetero(C₂₋₆)cycloalkyl, phenyl,hetero(C₂₋₅)aryl, (C₃₋₇)cycloalkylmethyl, hetero(C₂₋₆)cycloalkylmethyl,benzyl, and hetero(C₂₋₅)arylmethyl, each substituted or unsubstituted;

where

-   -   the hetero(C₂₋₆)cycloalkyl, hetero(C₂₋₆)cycloalkylmethyl,        hetero(C₂₋₅)aryl, and hetero(C₂₋₅)arylmethyl may contain up to        three heteroatoms as ring atoms, where each of the heteroatoms        is independently selected from the group consisting of nitrogen,        oxygen and sulfur atoms, and    -   the three, four, five, six and seven membered rings is        unsubstituted or optionally substituted with up to four        substituents each of which is independently selected from the        group consisting of halo, cyano, thio, amino, hydroxy, alkoxy,        aryloxy, heteroaryloxy, carbonyl, oxycarbonyl, alkoxycarbonyl,        aminocarbonyl, (C₁₋₁₀)alkylamino, amido, carboxamido,        sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₅)alkyl, sulfonyl(C₁₋₅)alkyl,        sulfinyl(C₁₋₅)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₂₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In another variation, R₂ is

where

-   -   J² is selected from the group consisting of —CR₁₆—, —N—;    -   each J³ is independently selected from the group consisting of        —CR₁₆XR₁₄—, —NR₁₇—, —O—, and —S—; and    -   not more than three J² and J³s together are —N—, —NR₁₇—, —O—, or        —S—,        -   where            -   each X is selected from a group consisting of a bond,                —O—, —C(O)—, —NR₁₅—, —NR₁₅C(O)—, —C(O)NR₁₅—,                —S(O)₂NR₁₅—, and —NR₁₅S(O)₂—; where R₁₅ is selected from                the group consisting of hydrogen, alkoxy, aryloxy,                heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,                (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,                hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,                heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,                hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, and                hetero(C₂₋₁₀)aryl, each substituted or unsubstituted,            -   each R₁₄ is independently selected from a group                consisting of hydrogen, halo, cyano, thio, amino,                hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,                oxycarbonyl, alkoxycarbonyl, aminocarbonyl,                (C₁₋₁₀)alkylamino, amido, carboxamido, sulfonamido,                sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,                alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,                thiocarbonyl(C₁₋₅)alkyl, sulfonyl(C₁₋₅)alkyl,                sulfinyl(C₁₋₅)alkyl, amino(C₁₋₁₀)alkyl,                imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,                hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,                heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,                hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,                hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,                hetero(C₂₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl,                hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, and                hetero(C₄₋₁₂)bicycloaryl, each substituted or                unsubstituted,            -   R₁₆ is independently selected from the group consisting                of hydrogen, halo, alkyl, hydroxyl, and alkoxy, each                substituted or unsubstituted, or R₁₆ may be absent when                the carbon to which it is bound forms a double bond,            -   each R₁₇ is independently selected from the group                consisting of hydrogen, alkyl, and alkoxy, each                substituted or unsubstituted, or R₁₇ may be absent when                the nitrogen to which it is bound forms a double bond,                and            -   any two adjacent R₁₆, or R₁₇, or R₁₆ and R₁₇ may be                taken together to form a substituted or unsubstituted                ring.

In another variation, R₂ is

wherein

-   -   J² is selected from the group consisting of —CR₁₆—, —N—;    -   each J⁴ is independently selected from the group consisting of        —CR₁₆XR₁₄— and —NR₁₇—; and    -   not more than two J² and J⁴ together are —N—, or —NR₁₇—,        -   where        -   each X is selected from a group consisting of a bond, —O—,            —S—, —C(O)—, —NR₁₅—, —NR₁₅C(O)—, —C(O)NR₁₅—, —S(O)₂NR₁₅—,            and —NR₁₅S(O)₂—, where R₁₅ is selected from the group            consisting of hydrogen, alkoxy, aryloxy, heteroaryloxy,            (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl,            each substituted or unsubstituted,        -   each R₁₄ is independently selected from a group consisting            of hydrogen, halo, cyano, thio, amino, hydroxy, alkoxy,            aryloxy, heteroaryloxy, carbonyl, oxycarbonyl,            alkoxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, amido,            carboxamido, sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,            halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,            thiocarbonyl(C₁₋₅)alkyl, sulfonyl(C₁₋₅)alkyl,            sulfinyl(C₁₋₅)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,            hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,            hetero(C₂₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,            (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each            substituted or unsubstituted;        -   R₁₆ is independently selected from the group consisting of            hydrogen, halo, alkyl, hydroxyl, and alkoxy, each            substituted or unsubstituted, or R₁₆ may be absent when the            carbon to which it is bond forms a double bond,        -   each R₁₇ is independently selected from the group consisting            of hydrogen, alkyl, and alkoxy, each substituted or            unsubstituted, or R₁₇ may be absent when the nitrogen to            which it is bond forms a double bond, and        -   any two adjacent R₁₆s, or R₁₇s, or R₁₆ and R₁₇ may be taken            together to form a ring.

In another variation, R₂ is selected from the group consisting of

wherein

-   -   X is selected from the group consisting of a bond, —O—, —S—,        —C(O)—, and —NR₁₅—; and    -   (i) when X is a bond, R₁₄ is selected from the group consisting        of hydrogen, halo, cyano, alkyl, amino,

-   -   -   where            -   R₃₉ is selected from the group consisting of hydrogen,                (C₁₋₆)alkyl, halo(C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₄₋₆)aryl,                hetero(C₂₋₅)aryl, each substituted or unsubstituted,

    -   (ii) when X is ═O— or —S—, R₁₄ is selected from the group        consisting of

-   -   -   where            -   w is 0, 1 or 2,            -   R₁₈ is selected from the group consisting of hydrogen,                (C₁₋₆)alkyl, (C₁₋₆)alkoxy, halo(C₁₋₆)alkyl, (C₄₋₆)aryl,                hetero(C₂₋₅)aryl, each substituted or unsubstituted,            -   R₁₉ is selected from the group consisting of hydrogen,                (C₁₋₆)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,                (C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl, each substituted or                unsubstituted,            -   R₃₄ is selected from the group consisting of                (C₁₋₆)alkyl, amino, (C₁₋₆)alkylamino,                hetero(C₂₋₅)cycloalkyl, and            -   R₃₅ is selected from the group consisting of halo,                (C₁₋₆)alkoxy;

    -   (iii) when X is —C(O)—, R₁₄ is selected from the group        consisting of

-   -   (iv) when X is —NR₁₅— and R₁₅ is hydrogen or alkyl, R₁₄ is        selected from the group consisting of hydrogen and alkyl.

In another variation, R₂ is selected from the group consisting of—(CH₂)_(r)NHC(O)R₂₀, —(CH₂)_(r)NHS(O)₂R₂₀, —(CH₂)_(r)NHC(O)NHR₂₀, and—(CH₂)_(r)NHC(O)OR₂₀,

wherein

-   -   r is 2 or 3, and    -   R₂₀ is selected from the group consisting of alkyl, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, cycloalkylmethyl,        heterocycloalkylmethyl, arylmethyl, and heteroarylmethyl, each        unsubstituted or substituted.

In one variation of the above variation, R₂₀ is aryl or aryl methylselected from the group consisting of unsubstituted or substituted phenyand unsubstituted or substituted benzyl, where the substituents on thephenyl and benzyl are selected from the group consisting of fluoro,chloro, methyl, ethyl, and methoxy. In other variations, R₂₀ ishetero(C₁₋₆)aryl.

In another variation of the above variation, R₂₀ is alkyl. In somevariations, R₂₀ is (C₁₋₆)alkyl. In other variations, R₂₀ is selectedfrom the group consisting of methyl, ethyl, isopropyl, and isobutyl. Inanother variation of the above variation, R₂₀ is cyclohexyl. In othervariations, R₂₀ is heterocyclo(C₁₋₆) alkyl.

In another variation, R₂ is selected from the group consisting ofmethyl, isobutyl, —CH₂C(O)NH₂, —CH₂CH₂OCH₃, —CH₂CH₂═CH₂,

In another further variation, R₂ is selected from the group consistingof —CH₂C(O)NH₂, —CH₂CH₂OCH₃,

In another variation, R₂ is selected from the group consisting of

where

-   -   R₄₀ is H, fluoro, chloro, methyl, or methoxy; and    -   R₄₁ is isopropyl or isobutyl

In another variation, R₂ is selected from the group consisting ofmethyl, —CH₂CH₂═CH₂,

In another variation, R₂ is selected from the group consisting ofisobutyl, —CH₂C(O)NH₂, —CH₂CH₂═CH₂,

where R₄₀ is H, fluoro, chloro, methyl, or methoxy

In another variation, R₂ is selected from the group consisting of—CH₂CH₂═CH₂,

In another variation, R₂ is selected from the group consisting ofmethyl, —CH₂C(O)NH₂, —CH₂CH₂═CH₂,

In one variation, R₃ is selected from the group consisting of hydrogen,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each unsubstituted orsubstituted with up to four substituents.

In another variation, R₃ is a five or six membered ring selected fromthe group consisting of (C₅₋₆)cycloalkyl, hetero(C₁₋₆)cycloalkyl,(C₅₋₆)aryl, and hetero(C₁₋₆)aryl, where the hetero(C₁₋₆)cycloalkyl andthe hetero(C₁₋₆)aryl may contain up to four heteroatoms as ring atoms,where the heteroatoms are each independently selected from the groupconsisting of nitrogen, oxygen and sulfur atoms and where the five orsix membered ring may be unsubstituted or substituted with up to foursubstituents. In another variation, R₃ is a six membered ring selectedfrom the group consisting of (C₆)cycloalkyl, hetero(C₃₋₆)cycloalkyl,(C₆)aryl, and hetero(C₃₋₆)aryl, where the hetero(C₆)cycloalkyl and thehetero(C₆)aryl may contain up to three nitrogen atoms as ring atoms, andwhere six membered ring may be unsubstituted or substituted with up tofour substituents. In another variation, R₃ is phenyl, an unsubstitutedor substituted with up to four substituents. In another variation, R₃ iscyclohexyl, unsubstituted or substituted with up to four substituents.

In the above variations, the up to four substitutents on R₃ are eachindependently selected from the group consisting of halo, cyano, thio,amino, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl, oxycarbonyl,alkoxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, amido, carboxamido,sulfonamido, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and any twoadjacent substituents on R₃ may be taken together to form a five, six orseven membered ring, each substituted or unsubstituted.

In another variation, the up to four substituents on R₃ are eachindependently selected from the group consisting of hydrogen, nitro,hydroxy, alkoxy, alkyl, alkylsulfonyl, heteroalkyl, cycloalkyl,cycloheteroalkyl, alkoxyalkyl, alkoxyalkylthio, amidoalkyl,alkylamidoalkyl, carboxyamidoalkyl, alkylcarboxyamidoalkyl, and

-   -   wherein        -   o is 0, 1, or 2,        -   s is 1, 2, 3, or 4,        -   t is 0, 1, 2, 3, or 4,        -   u is 0, 1, 2, 3, or 4,        -   D² is —C(O)—, —S(O)— and —S(O)₂—,        -   E is selected from the group consisting of hydrogen,            hydroxyl and alkoxy,        -   G¹ is selected from the group consisting of —CH₂—, —O—, and            —S—,        -   G² is selected from the group consisting of hydrogen,            hydroxy, (C₁₋₁₀)alkoxy, aryl, heteroaryl, —C(O)R₂₁,            —S(O)R₂₁, and —S(O)₂R₂₁, wherein R₂₁ is selected from the            group consisting of hydrogen, hydroxyl, alkoxy, alkyl, aryl,            and heteroaryl,        -   Z is selected from the group consisting of hydrogen,            hydroxyl, alkoxy, alkyl, and —NHC(O)alkyl,        -   R₂₄ is selected from the group consisting of hydrogen,            alkyl, alkoxy, aryl, and heteroaryl, each substituted or            unsubstituted,        -   R₃₃ is selected from the group consisting of hydrogen,            (C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, (C₁₋₆)alkoxy(C₁₋₆)alkyl,            aryl, and heteroaryl, each substituted or unsubstituted,        -   R₃₆ is selected from the group consisting of hydrogen,            (C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, (C₁₋₆)alkoxy(C₁₋₆)alkyl,            each substituted or unsubstituted,        -   each R₃₇ is independently selected from the group consisting            of hydrogen, (C₁₋₈)alkyl, (C₁₋₄)alkoxy(C₁₋₈)alkyl, each            substituted or unsubstituted, and        -   each R₃₈ is independently selected from the group consisting            of (C₁₋₈)alkyl, (C₁₋₈)alkoxy, (C₁₋₄)alkoxy(C₁₋₈)alkyl, and            —(C₁₋₈)alkyl-NHC(O)(C₁₋₄)alkyl.

In another variation, R₃ is selected from the group consisting of

wherein

-   -   o is 0, 1, or 2,    -   s is 1, 2, 3, or 4,    -   t is 0, 1, 2, 3, or 4,    -   u is 0, 1, 2, 3, or 4,    -   E is selected from the group consisting of hydrogen, hydroxyl        and alkoxy,    -   G¹ is selected from the group consisting of —CH₂—, —O—, and —S—,    -   G² is selected from the group consisting of hydrogen, hydroxy,        (C₁₋₁₀)alkoxy, aryl, heteroaryl, —C(O)R₂₁, —S(O)R₂₁, and        —S(O)₂R₂₁, wherein R₂₁ is selected from the group consisting of        hydrogen, hydroxyl, alkoxy, alkyl, aryl, and heteroaryl,    -   Z is selected from the group consisting of hydrogen, hydroxyl,        alkoxy, alkyl, and —NHC(O)alkyl,    -   R₂₂ is selected from the group consisting of hydrogen, alkyl,        aryl, and heteroaryl,    -   R₂₃ is selected from the group consisting of hydrogen, alkyl,        heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl,        and alkoxyalkylthio,    -   R₃₃ is selected from the group consisting of hydrogen,        (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₁₋₆)heterocyclo alkyl,        hydroxy(C₁₋₆)alkyl, (C₁₋₆)alkoxy(C₁₋₆)alkyl, aryl, and        heteroaryl,    -   R₃₆ is selected from the group consisting of hydrogen,        (C₁₋₆)alkyl, hydroxy(C₁₋₆)alkyl, (C₁₋₆)alkoxy(C₁₋₆)alkyl, and    -   R₃₇ is selected from the group consisting of hydrogen,        (C₁₋₈)alkyl, (C₁₋₄)alkoxy(C₁₋₈)alkyl.

In another variation, R₃ is selected from the group consisting of

In another variation, R₃ is selected from the group consisting of

wherein

-   -   o is 0, 1, or 2;    -   s is 1, 2, 3, or 4;    -   y is 1 or 2;    -   D² is selected from the group consisting of —C(O)—, —S(O)— and        —S(O)₂—;    -   D³ is selected from the group consisting of —C(═S)—, —C(═O)—,        and —C(═NR₁₂)—, where R₁₂ is selected from the group consisting        of hydrogen, hydroxyl, alkoxy, aryloxy, heteroaryloxy,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₄)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂) aryl, hetero(C₂₋₁₀)aryl, each        substituted or unsubstituted;    -   G¹ is selected from the group consisting of —CH₂—, —O—, and —S—;    -   G² is selected from the group consisting of hydrogen, hydroxy,        (C₁₋₁₀)alkoxy, aryl, heteroaryl, —C(O)R₂₁, —S(O)R₂₁, and        —S(O)₂R₂₁, wherein R₂₁ is selected from the group consisting of        hydrogen, hydroxyl, alkoxy, alkyl, aryl, and heteroaryl;    -   R₂₂ is selected from the group consisting of hydrogen, alkyl,        aryl, and heteroaryl;    -   R₂₄ is selected from the group consisting of hydrogen, alkyl,        alkoxy, aryl, and heteroaryl, each substituted or unsubstituted;    -   R₃₇ is selected from the group consisting of hydrogen,        (C₁₋₈)alkyl, (C₁₋₄)alkoxy(C₁₋₈)alkyl; and    -   R₃₈ are independently selected from the group consisting of        hydrogen, (C₁₋₈)alkyl, (C₁₋₈)alkoxy, (C₁₋₄)alkoxy(C₁₋₈)alkyl,        and —(C₁₋₈)alkyl-NHC(O)(C₁₋₄)alkyl.

In another variation, R₃ is selected from the group consisting of

In another variation, R₃ is selected from the group consisting of

wherein

-   -   R₂₄ is selected from the group consisting of hydrogen, alkyl,        aryl, and heteroaryl;    -   R₃₇ is selected from the group consisting of hydrogen,        (C₁₋₈)alkyl, (C₁₋₄)alkoxy(C₁₋₈)alkyl; and    -   R₃₈ are independently selected from the group consisting of        (C₁₋₈)alkyl, (C₁₋₄)alkoxy(C₁₋₈)alkyl, and        —(C₁₋₈)alkyl-NHC(O)(C₁₋₄)alkyl.

In another variation, R₃ is selected from the group consisting of:

In another variation, R₃ is selected from the group consisting of:

In one variation, R₄ when present is selected from the group consistingof hydrogen, oxo, (C₁₋₄₀)alkoxy, (C₁₋₁₀)alkoxy(C₁₋₃)alkyl,(C₁₋₆)alkylthio(C₁₋₃)alkyl, (C₁₋₁₀)alkoxycarbonyl, aminocarbonyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl, (C₁₋₆)alkylthio(C₁₋₃)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,amido(C₁₋₁₀)alkyl, carboxamido(C₁₋₁₀)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl,aryloxy(C₁₋₅)alkyl, heteroaryloxy(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl, eachsubstituted or unsubstituted.

In another variation, R₄ when present is selected from the groupconsisting of hydrogen, (C₁₋₁₀)alkyl, (C₁₋₁₀)alkoxy, —CH₂—R₂₅,

wherein:

v is 0, 1, 2, 3 or 4;

R₂₅ is a six membered saturated, unsaturated or aromatic ring which maycontain up to four nitrogen atoms as ring atoms, and R₂₅ may besubstituted with up to four substituents, wherein each of thesubstituent is independently selected from the group consisting of halo,(C₁₋₁₀)alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl, eachsubstituted or unsubstituted;

R₂₆ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,(C₉₋₁₂)bicycloalkyl, hetero(C₄₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, andhetero(C₁₋₁₀)aryl, each substituted or unsubstituted; and

R₂₇ and R₂₈ are each independently selected from the group consisting ofhydrogen, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl, carbonyl,hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted.

In another variation, wherein R₄ when present is selected from the groupconsisting of hydrogen, (C₁₋₆)alkyl, —CH₂—R₂₅,

wherein

v is 0, 1, 2, 3 or 4;

R₂₅ is a 6-membered saturated, unsaturated or aromatic carbocycle whichmay be substituted with up to four substituents, wherein eachsubstituent is independently selected from the group consisting of halo,(C₁₋₁₀)alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,(C₅₋₁₂)aryl(C₁₋₅)alkyl, hetero(C₂₋₁₀)aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, eachsubstituted or unsubstituted;

R₂₆ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, (C₅₋₁₂)aryl(C₁₋₅)alkyl,hetero(C₂₋₁₀)aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, each substituted or unsubstituted;

R₂₇ and R₂₈ are each independently selected from the group consisting ofhydrogen, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,(C₅₋₁₂)aryl(C₁₋₅)alkyl, hetero(C₂₋₁₀)aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,(C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted; and

R₂₉ is selected from the group consisting of hydrogen, alkyl, amidoalkylcarboxamidoalkyl, alkoxycarbonylalkyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heterarylalkyl, cycloalkylalkyl, andheterocycloalkylalkyl, each substituted and unsubstituted.

In another variation, R₄ when present is selected from the groupconsisting of hydrogen, (C₁₋₆)alkyl, —CH₂—R₂₅, —CH₂N(R₂₈)C(O)R₂₉,

wherein

-   -   R₂₅ is a 6-membered saturated, unsaturated or aromatic        carbocycle which may be substituted with up to four        substituents, wherein each substituent is independently selected        from the group consisting of alkyl, halo and (C₁₋₁₀)alkoxy, each        substituted or unsubstituted;    -   R₂₈ is selected from the group consisting of hydrogen,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl,        each substituted or unsubstituted; and    -   R₂₉ is selected from the group consisting of hydrogen, alkyl,        amidoalkyl carboxamidoalkyl, alkoxycarbonylalkyl, (C₅₋₁₂)aryl,        hetero(C₂₋₁₀)aryl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,        (C₅₋₁₂)aryl(C₁₋₅)alkyl, heteraryl(C₂₋₁₀)aryl(C₁₋₅)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, and        hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, each substituted and        unsubstituted.

In another variation, R₄ when present is selected from the groupconsisting of hydrogen, benzyl,

In another variation, R₄ when present is selected from the groupconsisting of hydrogen and benzyl.

In another variation, R₄ when present is benzyl.

In another variation, R₄ when present is hydrogen.

In another variation, R₄ when present is

In another variation, R₄ when present is

In another variation, R₄ when present is —CH₂-phenyl where the phenyl issubstituted with up to two substituents and each of the substituent isindependently selected from the group consisting of ═OR₃₀, —NHR₃₁ and—C(O)NHR₃₁,

wherein

R₃₀ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₃₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and

R₃₁ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,carboxamido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another variation, R₄ when present is selected from the groupconsisting of hydrogen, —CH₂N(R₂₈)C(O)R₂₉, and —(CH₂)_(n)—O—R₂₈,

wherein

n is 1, 2, or 3;

R₂₈ is selected from the group consisting of hydrogen, (C₁₋₆)alkyl andaryl, each substituted or unsubstituted; and

R₂₉ is selected from the group consisting of hydrogen, alkyl, aryl,—CH₂C(CH₃)₂C(O)OCH₃, and —CH₂C(CH₃)₂C(O)NR₃₂R_(32′), wherein R₃₂ andR_(32′) are each independently selected from the group consisting ofhydrogen, alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclic alkyl,each substituted or unsubstituted.

In one variation, R₇ when present is selected from the group consistingof hydrogen, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, (C₁₋₁₀)alkoxy,(C₅₋₁₂)aryloxy, hetero(C₂₋₄₀)aryloxy, carbonyl(C₁₋₃)alkyl,carboxamidoalkyl, amidoalkyl, sulfonyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,(C₁₋₁₀)alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, each substituted or unsubstituted, orwhere R₇ and a substituent of L, Q, C^(a), or A are taken together toform a ring.

In another variation, R₇ when present is selected from the groupconsisting of hydrogen, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, (C₁₋₁₀)alkoxy,(C₅₋₈)aryloxy, hetero(C₄₋₇)aryloxy, carbonyl(C₁₋₃)alkyl,carboxamido(C₁₋₅)alkyl, amino(C₁₋₅)alkyl, (C₁₋₄₀)alkoxy(C₁₋₃)alkyl,(C₃₋₈)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₆)cycloalkyl(C₁₋₅)alkyl,aryl(C₅₋₈) alkyl, hetero(C₄₋₇)aryl(C₁₋₅)alkyl, (C₃₋₈)cycloalkyl,hetero(C₂₋₆)cycloalkyl, (C₅₋₈)aryl, hetero(C₄₋₇)aryl, each substitutedor unsubstituted, or where R₇ and a substituent of L, Q, C^(a), or A aretaken together to form a ring.

In another variation, R₇ when present is selected from the groupconsisting of hydrogen and alkyl.

In another variation, R₇ when present is hydrogen.

In another variation, R₉ when present is selected from the groupconsisting of hydrogen and substituted or unsubstituted (C₁₋₁₀)alkyl.

In one embodiment, the compound of the invention consisting of theformula,

wherein

R₁ is phenyl;

R₂ is selected from all the variations disclosed above;

R₃ is selected from the group consisting of

and

R₄ is selected from the group consisting of

Examples of compounds according to the present invention include, butare not limited to:

-   (S)-1-((2-Chloro-6-(3-hydroxypyrrolidin-1-yl)pyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   (R)-1-((2-Chloro-6-(3-hydroxypyrrolidin-1-yl)pyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-((2,6-bis((R)-3-Hydroxypyrrolidin-1-yl)pyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-((2,6-bis((S)-3-Hydroxypyrrolidin-1-yl)pyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-Cyclohexyl-3((2,6-di(2methoxyl-pyridine-4-yl)pyridin-4-yl)methyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-Cyclohexyl-3((6′-methoxy-2,3′-bipyridin-4-yl)methyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1((6-Chloro-6′-methoxy-2,3′-bipyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-Cyclohexyl-3((6-(dimethylamino)-6′-methoxy-2,3′-bipyridin-4-yl)methyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-Cyclohexyl-3((6-(diethylamino)-6′-methoxy-2,3′-bipyridin-4-yl)methyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1,5-Diphenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   5-Phenyl-4-(piperazine-1-carbonyl)-1-(pyridin-2-yl)-1H-imidazol-2(3H)-one;-   4-(2-(Hydroxymethyl)piperazine-1-carbonyl)-1,5-diphenyl-1H-imidazol-2(3H)-one;-   5-(3-Fluorophenyl)-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-Morpholinophenyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   5-Isopropyl-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   5-Cyclopropyl-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   5-(Cyclopropylmethyl)-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   5-(2-Chlorophenyl)-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   5-(3-Chlorophenyl)-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   5-(4-Chlorophenyl)-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-Cyclohexyl-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   Benzyl    3-(2-oxo-5-phenyl-4-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate;-   1-((1R,2R)-2-(Benzyloxy)cyclohexyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(2-(2-Methoxyethoxy)phenyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(2-(3-Methoxypropoxy)phenyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-(2-Methoxyethoxy)phenyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-(3-Methoxypropoxy)phenyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(6-(3-Methoxypropoxy)pyridin-2-yl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   (R)-1-Cyclohexyl-4-(3-methylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one;-   1-Cyclohexyl-4-(3-methylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one;-   (S)-1-Cyclohexyl-4-(3-methylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one;-   1-Cyclohexyl-4-(3,5-dimethylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one;-   1-Cyclohexyl-4-(2,5-dimethylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one;-   5-(3-Chlorophenyl)-1-(3-(3-methoxypropoxy)phenyl)-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   5-(3-Chlorophenyl)-1-(3-(2-methoxyethoxy)phenyl)-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(1H-Benzo[d]imidazol-2-yl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-Benzyl-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-Benzyl-4-phenyl-5-(piperazine-1-carbonyl)-3-(pyridin-2-yl)-1H-imidazol-2(3H)-one;-   1-((5-Methylisoxazol-3-yl)methyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)methyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-((1H-Imidazol-4-yl)methyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-((2-Aminothiazol-4-yl)methyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-Fluorobenzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3,4-Difluorobenzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1,5-Diphenyl-4-(piperazine-1-carbonyl)-3-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-2(3H)-one;-   1-Methyl-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-3-methyl-1-(3-morpholinophenyl)-5-phenyl-1H-imidazol-2(3H)-one;-   1-Benzyl-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-(Morpholine-4-carbonyl)benzyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-Morpholinophenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-(3-(piperidine-1-carbonyl)benzyl)-1H-imidazol-2(3H)-one;-   2-(3-((3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)phenoxy)acetic    acid;-   1-Cyclohexyl-3-methyl-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-Allyl-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   2-(3-Cyclohexyl-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)acetamide;-   (R)-1-Allyl-5-(2-benzylpiperazine-1-carbonyl)-3-cyclohexyl-4-phenyl-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-1-cyclohexyl-3-methyl-5-phenyl-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-1-cyclohexyl-3-(2-methoxyethyl)-5-phenyl-1H-imidazol-2(3H)-one;-   (R)-2-(5-(2-Benzylpiperazine-1-carbonyl)-3-cyclohexyl-2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)acetamide;-   Methyl    2-(3-cyclohexyl-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)-2-phenylacetate;-   1-Cyclohexyl-5-phenyl-3-(1-phenylethyl)-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-1-cyclohexyl-3-methyl-5-phenyl-1H-imidazol-2(3H)-one;-   1-Cyclohexyl-3-phenethyl-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-(1H-Pyrrol-1-yl)benzyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   (R)-2-(5-(2-Benzylpiperazine-1-carbonyl)-2-oxo-3,4-diphenyl-2,3-dihydro-1H-imidazol-1-yl)acetamide;-   1-(3-Morpholinophenyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-(3-Methoxypropoxy)phenyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-(Benzyloxy)benzyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-(1H-Pyrrol-1-yl)benzyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   N-Isobutyl-N-methyl-3-((3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)benzamide;-   3-((2-O-oxo-3,4-Diphenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)benzonitrile;-   Methyl    3-((2-oxo-3,4-Diphenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)benzoate;-   1-Benzyl-4-phenyl-5-(piperazine-1-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2(3H)-one;-   1,5-Diphenyl-4-(piperazine-1-carbonyl)-3-(quinolin-8-ylmethyl)-1H-imidazol-2(3H)-one;-   1-(3-Methoxybenzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(Naphthalen-2-ylmethyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   2-((2-oxo-3,4-Diphenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)benzonitrile;-   1-(3,5-Dimethoxybenzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(4-Chloro-3-(trifluoromethoxy)benzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-(1H-Pyrrol-1-yl)benzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-Cyclohexyl-4-(1,4-diazepane-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one;-   1-((2-Chloro-6-morpholinopyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-Cyclohexyl-3-((2,6-di(1H-pyrazol-4-yl)pyridin-4-yl)methyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(1-Acetylpiperidin-3-yl)-3-(3-methoxybenzyl)-5-phenyl-4-(piperazine-1carbonyl)-1H-imidazol-2(3H)-one;-   1-(1-Acetylpiperidin-3-yl)-3-benzyl-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(1-Acetylpiperidin-3-yl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(1-Benzoylpiperidin-3-yl)-3-benzyl-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-Benzyl-4-phenyl-3-(1-(phenylsulfonyl)piperidin-3-yl)-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-Benzyl-3-(1-(furan-2-carbonyl)piperidin-3-yl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   5-Phenyl-1-(1-(phenylsulfonyl)piperidin-3-yl)-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(1-Acetylpiperidin-3-yl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-Benzyl-4-phenyl-3-(1-(phenylsulfonyl)piperidin-3-yl)-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-Benzyl-4-phenyl-5-(piperazine-1-carbonyl)-3-(1-(pyridin-2-ylsulfonyl)piperidin-3-yl)-1H-imidazol-2(3H)-one;-   1-(3-Phenoxybenzyl)-4-phenyl-3-(1-(phenylsulfonyl)piperidin-3-yl)-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-Phenoxybenzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-(1-(pyridin-2-ylsulfonyl)piperidin-3-yl)-1H-imidazol-2(3H)-one;-   1-(1-Acetylpiperidin-3-yl)-4-((R)-2-benzylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one;-   1-Benzyl-3-((1R,2R)-2-hydroxycyclohexyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-((1R,2R)-2-Hydroxycyclohexyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   N—(((S)-1-(1-((1R,2R)-2-Hydroxycyclohexyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazin-2-yl)methyl)benzamide;-   (S)—N-((1-(1-Cyclohexyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazin-2-yl)methyl)benzamide;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-1,5-diphenyl-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(3-morpholinophenyl)-5-phenyl-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-1-cyclohexyl-5-phenyl-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(2,3-dimethoxyphenyl)-5-phenyl-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(2-methoxyphenyl)-5-phenyl-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(3-(methylsulfonyl)phenyl)-5-phenyl-1H-imidazol-2(3H)-one;-   1-(1-Acetylpiperidin-3-yl)-4-((R)-2-benzylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-5-phenyl-1-o-tolyl-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(2-nitrophenyl)-5-phenyl-1H-imidazol-2(3H)-one;-   (R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)methanesulfonamide;-   (R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)propane-1-sulfonamide;-   (R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)cyclopropanecarboxamide;-   (R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)butyramide;-   (R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)acetamide;-   (R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)cyclopropanesulfonamide;-   (R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)benzamide;-   (R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)Benzenesulfonamide;-   4-((R)-2-Benzylpiperazine-1-carbonyl)-14(1S,2S)-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-2(3H)-one;-   (R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)ethanesulfonamide;-   (R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)butane-1-sulfonamide;-   (R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)prop-2-ene-1-sulfonamide;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-1-((1-hydroxycyclohexyl)methyl)-5-phenyl-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-5-phenyl-1-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-5-phenyl-1-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(1-butyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-cyclopropyl-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-5-cyclopropyl-1-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-phenyl-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(indolin-6-yl)-5-phenyl-1H-imidazol-2(3H)-one;-   (R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(4-(2-methoxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-phenyl-1H-imidazol-2(3H)-one;-   4-((R)-2-Benzylpiperazine-1-carbonyl)-1-(3-methoxy-2,3-dihydro-1H-inden-5-yl)-5-phenyl-1H-imidazol-2(3H)-one;-   (S)-(6-(4-(2-Benzylpiperidine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)indolin-1-yl)methyl    acetate;-   (R)-4-(2-(2-Phenoxyethyl)piperazine-1-carbonyl)-5-phenyl-1-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-imidazol-2(3H)-one.-   1-Allyl-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one;-   1-(3-Phenoxybenzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one;-   1-(3-Methoxybenzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one;-   1-(3,4-Difluorobenzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one;-   1-Allyl-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(2-Methoxyphenyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-Methoxybenzyl)-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3,4-Difluorobenzyl)-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-(2-Phenoxyethoxy)benzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one;-   1-Allyl-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-Methoxybenzyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-((1S,2R)-2-Hydroxycyclohexyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-((1S,2R)-2-Hydroxycyclohexyl)-3-(3-methoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3,4-Difluorobenzyl)-3-((1S,2R)-2-hydroxycyclohexyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   N-(2-(2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;-   N-(3-(2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;-   1-(Cyclohexylmethyl)-3-((1S,2R)-2-hydroxycyclohexyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   N-(2-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;-   N-(3-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;-   1-(Cyclohexylmethyl)-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   N-(3-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   N-(3-(2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   1-(Cyclohexylmethyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one;-   1-(3,4-Difluorobenzyl)-3-(3-(3-methoxypropoxy)phenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   3-Methyl-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)butanamide;-   N-(2-(2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;-   N-(3-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)-3-methylbutanamide;-   N-(2-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;-   N-(2-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)-3-methylbutanamide;-   N-(3-(3-((2S)-2-Hydroxycyclohexyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;-   N-(3-(3-((2S)-2-Hydroxycyclohexyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   N-(3-(3-((2S)-2-Hydroxycyclohexyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)-3-methylbutanamide;-   N-(2-(3-((2S)-2-Hydroxycyclohexyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)-3-methylbutanamide;-   N-(3-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazolidin-1-yl)propyl)benzamide;-   N-(3-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   3-Methyl-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)butanamide;-   N-(2-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;-   3-Methyl-N-(2-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)butanamide;-   N-(3-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;-   N-(3-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   N-(3-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)-3-methylbutanamide;-   N-(2-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;-   N-(2-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;-   N-(2-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)-3-methylbutanamide;-   N-(2-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;-   1-(3-(2-Methoxyethoxy)benzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one;-   1-(3-(2-Methoxyethoxy)benzyl)-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(2-Methoxyphenyl)-3-(3-(2-phenoxyethoxy)benzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(Cyclohexylmethyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3,4-Difluorobenzyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-Morpholinophenyl)-3-(3-(2-phenoxyethoxy)benzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   1-(3-(2-Methoxyethoxy)benzyl)-3-(3-(3-methoxypropoxy)phenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;-   2-Fluoro-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   2-Chloro-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   3-Chloro-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   N-(3-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)propane-2-sulfonamide;-   2-Methyl-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   3-Methoxy-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   4-Methoxy-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   1-(3-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)-3-phenylurea;-   1-Isopropyl-3-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)urea;-   4-Chloro-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   2-Fluoro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;-   2-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;-   3-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;-   4-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;-   N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)propane-2-sulfonamide;-   2-Methyl-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;-   3-Methoxy-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;-   4-Methoxy-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;-   1-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)-3-phenylurea;-   1-(2-Chlorophenyl)-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea;-   1-(4-Chlorophenyl)-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea;-   1-(2-Methoxyphenyl)-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea;-   1-(3-Methoxyphenyl)-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea;-   1-Isopropyl-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea;-   2-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   3-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   4-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   2-Methyl-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   3-Methoxy-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   4-Methoxy-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   1-(3-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)-3-phenylurea;-   1-(2-Chlorophenyl)-3-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)urea;-   1-(2-Methoxyphenyl)-3-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)urea;-   1-(3-Methoxyphenyl)-3-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)urea;-   1-Isopropyl-3-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)urea;-   1-(4-Methoxyphenyl)-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea;-   2-Fluoro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;-   2-Fluoro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;-   2-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;-   2-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;-   3-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;-   4-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;-   2-Methoxy-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;-   4-Methoxy-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;-   N-(2-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)isobutyramide;-   N-(2-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)cyclohexanecarboxamide-   3-Methyl-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)butanamide;-   N-(3-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)propane-2-sulfonamide;-   2-Fluoro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;-   2-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;-   3-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;-   4-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;-   2-Methoxy-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;-   4-Methoxy-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;-   N-(3-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)isobutyramide;-   N-(3-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)cyclohexanecarboxamide;-   Phenyl    2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethylcarbamate;-   Methyl    2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethylcarbamate;-   Ethyl    2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethylcarbamate;-   Benzyl    2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethylcarbamate;-   Phenyl    3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propylcarbamate;-   Methyl    3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propylcarbamate;-   Ethyl    3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propylcarbamate;-   Benzyl    3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propylcarbamate;-   1-(2-Methylphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-2-one;-   1-(Cyclohexylmethyl)-3-(2-methylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-(2-Methylphenyl)-3-[(3-phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(2-Amino1,3-thiazol-4-yl)methyl]-3-(2-methylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(3-Methoxyphenyl)methyl]-3-(2-methylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(3,4-Difluorophenyl)methyl]-3-(2-methylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   N-[2-[3-(2-Methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzamide;-   N-[2-[3-(2-Methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzenesulfonamide;-   3-Methyl-N-[2-[3-(2-methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]butanamide;-   2-Methyl-N-[2-[3-(2-methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]propane-1-sulfonamide;-   N-[3-[3-(2-Methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzamide;-   N-[3-[3-(2-Methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzenesulfonamide;-   3-Methyl-N-[3-[3-(2-methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]butanamide;-   2-Methyl-N-[3-[3-(2-methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]propane-1-sulfonamide;-   1-[[3-(2-Methoxyethoxy)phenyl]methyl]-3-(2-methylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-(2-Methylphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-2-one;-   1-(2-Methylphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-2-one;-   1-(2-Methylphenyl)-3-[[3-(2-phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-(2-Methylphenyl)-3-[[3-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-(2-Methylphenyl)-3-[[3-[2-oxo-2-(1-piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   N-Methyl-2-[3-[[3-(2-methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]acetamide;-   2-[3-[[3-(2-Methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;-   1-(2-Methoxyphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-2-one;-   1-(Cyclohexylmethyl)-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-(2-Methoxyphenyl)-3-[(3-phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(2-Amino1,3-thiazol-4-yl)methyl]-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-(2-Methoxyphenyl)-3-[(3-methoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(3,4-Difluorophenyl)methyl]-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   N-[2-[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzamide;-   N-[2-[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzenesulfonamide;-   N-[2-[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-3-methyl-butanamide;-   N-[2-[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-2-methyl-propane-1-sulfonamide;-   N-[3-[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzamide;-   N-[3-[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzenesulfonamide;-   N-[3-[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-3-methyl-butanamide;-   N-[3-[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-2-methyl-propane-1-sulfonamide;-   1-[[3-(2-Methoxyethoxy)phenyl]methyl]-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-(2-Methoxyphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-2-one;-   1-(2-Methoxyphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-2-one;-   1-(2-Methoxyphenyl)-3-[[3-(2-phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-(2-Methoxyphenyl)-3-[[3-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-(2-Methoxyphenyl)-3-[[3-[2-oxo-2-(1-piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   2-[3-[[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-methyl-acetamide;-   2-[3-[[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;-   1-(3-Morpholin-4-ylphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-2-one;-   1-(Cyclohexylmethyl)-3-(3-morpholin-4-ylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-(3-Morpholin-4-ylphenyl)-3-[(3-phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(2-Amino    1,3-thiazol-4-yl)methyl]-3-(3-morpholin-4-ylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(3-Methoxyphenyl)methyl]-3-(3-morpholin-4-ylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(3,4-Difluorophenyl)methyl]-3-(3-morpholin-4-ylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   N-[2-[3-(3-Morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzamide;-   N-[2-[3-(3-Morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzenesulfonamide;-   3-Methyl-N-[2-[3-(3-morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]butanamide;-   2-Methyl-N-[2-[3-(3-morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]propane-1-sulfonamide;-   N-[3-[3-(3-Morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzamide;-   N-[3-[3-(3-Morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzenesulfonamide;-   3-Methyl-N-[3-[3-(3-morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]butanamide;-   2-Methyl-N-[3-[3-(3-morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]propane-1-sulfonamide;-   1-[[3-(2-Methoxyethoxy)phenyl]methyl]-3-(3-morpholin-4-ylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-(3-Morpholin-4-ylphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-2-one;-   1-(3-Morpholin-4-ylphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-2-one-   1-(3-Morpholin-4-ylphenyl)-3-[[3-(2-phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[[3-(2-Morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-3-(3-morpholin-4-ylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-(3-Morpholin-4-ylphenyl)-3-[[3-[2-oxo-2-(1-piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   N-Methyl-2-[3-[[3-(3-morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]acetamide;-   2-[3-[[3-(3-Morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;-   1-[3-(3-Methoxypropoxy)phenyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-2-one;-   1-(Cyclohexylmethyly)-3-[3-(3-methoxypropoxy)phenyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-[3-(3-Methoxypropoxy)phenyl]-3-[(3-phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(2-Amino    1,3-thiazol-4-yl)methyl]-3-[3-(3-methoxypropoxy)phenyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(3-Methoxyphenyl)methyl]-3-[3-(3-methoxypropoxy)phenyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(3,4-Difluorophenyl)methyl]-3-[3-(3-methoxypropoxy)phenyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   N-[2-[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzamide;-   N-[2-[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzenesulfonamide;-   N-[2-[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-3-methyl-butanamide;-   N-[2-[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-2-methyl-propane-1-sulfonamide;-   N-[3-[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzamide;-   N-[3-[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzenesulfonamide;-   N-[3-[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-3-methyl-butanamide;-   N-[3-[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-2-methyl-propane-1-sulfonamide;-   1-[[3-(2-Methoxyethoxy)phenyl]methyl]-3-[3-(3-methoxypropoxy)phenyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-[3-(3-Methoxypropoxy)phenyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-2-one;-   1-[3-(3-Methoxypropoxy)phenyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-2-one;-   1-[3-(3-Methoxypropoxy)phenyl]-3-[[3-(2-phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[3-(3-Methoxypropoxy)phenyl]-3-[[3-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[3-(3-Methoxypropoxy)phenyl]-3-[[3-[2-oxo-2-(1-piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   2-[3-[[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-methyl-acetamide;-   2-[3-[[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;-   N-[(1S)-2-[2-oxo-5-Phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-1-yl]cyclohexyl]propanamide;-   N-[(1S)-2-[3-(Cyclohexylmethyly)-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;-   N-[(1S)-2-[2-oxo-3-[(3-Phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;-   N-[(1S)-2-[3-[(2-Amino1,3-thiazol-4-yl)methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;-   N-[(1S)-2-[3-[(3-Methoxyphenyl)methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;-   N-[(1S)-2-[3-[(3,4-Difluorophenyl)methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;-   N-[2-[2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-[(2S)-2-(propanoylamino)cyclohexyl]imidazol-1-yl]ethyl]benzamide;-   N-[(1S)-2-[3-[2-(Benzenesulfonamido)ethyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;-   3-Methyl-N-[2-[2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-[(2S)-2-(propanoylamino)cyclohexyl]imidazol-1-yl]ethyl]butanamide;-   N-[(1S)-2-[3-[2-(2-Methylpropylsulfonylamino)ethyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;-   N-[3-[2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-[(2S)-2-(propanoylamino)cyclohexyl]imidazol-1-yl]propyl]benzamide;-   N-[(1S)-2-[3-[3-(Benzenesulfonamido)propyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;-   3-Methyl-N-[3-[2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-[(2S)-2-(propanoylamino)cyclohexyl]imidazol-1-yl]propyl]butanamide;-   N-[(1S)-2-[3-[3-(2-Methylpropylsulfonylamino)propyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;-   N-[(1S)-2-[3-[[3-(2-Methoxyethoxy)phenyl]methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;-   N-[(1S)-2-[2-oxo-5-Phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-1-yl]cyclohexyl]propanamide;-   N-[(1S)-2-[2-oxo-5-Phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-1-yl]cyclohexyl]propanamide;-   N-[(1S)-2-[2-oxo-3-[[3-(2-Phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;-   N-[(1S)-2-[3-[[3-(2-Morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;-   N-[(1S)-2-[2-oxo-3-[[3-[2-oxo-2-(1-Piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;-   N-[(1S)-2-[3-[[3-(Methylcarbamoylmethoxy)phenyl]methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;-   N-[(1S)-2-[2-oxo-5-Phenyl-4-(piperazine-1-carbonyl)-3-[[3-(propan-2-ylcarbamoylmethoxy)phenyl]methyl]imidazol-1-yl]cyclohexyl]propanamide;-   1-(1-Acetyl-3-piperidyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-2-one;-   1-(1-Acetyl-3-piperidyl)-3-(cyclohexylmethyl)-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-(1-Acetyl-3-piperidyl)-3-[(3-phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-(1-Acetyl-3-piperidyl)-3-[(2-amino1,3-thiazol-4-yl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-(1-Acetyl-3-piperidyl)-3-[(3-methoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-(1-Acetyl-3-piperidyl)-3-[(3,4-difluorophenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   N-[2-[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzamide;-   N-[2-[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzenesulfonamide;-   N-[2-[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-3-methyl-butanamide;-   N-[2-[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-2-methyl-propane-1-sulfonamide;-   N-[3-[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzamide;-   N-[3-[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzenesulfonamide;-   N-[3-[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-3-methyl-butanamide;-   N-[3-[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-2-methyl-propane-1-sulfonamide;-   1-(1-Acetyl-3-piperidyl)-3-[[3-(2-methoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-(1-Acetyl-3-piperidyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-2-one;-   1-(1-Acetyl-3-piperidyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-2-one;-   1-(1-Acetyl-3-piperidyl)-3-[[3-(2-phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-(1-Acetyl-3-piperidyl)-3-[[3-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-(1-Acetyl-3-piperidyl)-3-[[3-[2-oxo-2-(1-piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   2-[3-[[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-methyl-acetamide;-   2-[3-[[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;-   1-[1-(Benzenesulfonyl)-3-piperidyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-2-one;-   1-[1-(Benzenesulfonyl)-3-piperidyl]-3-(cyclohexylmethyl)-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[1-(Benzenesulfonyl)-3-piperidyl]-3-[(3-phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(2-Amino1,3-thiazol-4-yl)methyl]-3-[1-(benzenesulfonyl)-3-piperidyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-[1-(Benzenesulfonyl)-3-piperidyl]-3-[(3-methoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[1-(Benzenesulfonyl)-3-piperidyl]-3-[(3,4-difluorophenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   N-[2-[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzamide;-   N-[2-[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzenesulfonamide;-   N-[2-[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-3-methyl-butanamide;-   N-[2-[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-2-methyl-propane-1-sulfonamide;-   N-[3-[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzamide;-   N-[3-[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzenesulfonamide;-   N-[3-[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-3-methyl-butanamide;-   N-[3-[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-2-methyl-propane-1-sulfonamide;-   1-[1-(Benzenesulfonyl)-3-piperidyl]-3-[[3-(2-methoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[1-(Benzenesulfonyl)-3-piperidyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-2-one;-   1-[1-(Benzenesulfonyl)-3-piperidyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-2-one;-   1-[1-(Benzenesulfonyl)-3-piperidyl]-3-[[3-(2-phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[1-(Benzenesulfonyl)-3-piperidyl]-3-[[3-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[1-(Benzenesulfonyl)-3-piperidyl]-3-[[3-[2-oxo-2-(1-piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   2-[3-[[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-methyl-acetamide;-   2-[3-[[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;-   N-[2-[2-oxo-5-Phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-1-yl]phenyl]propane-1-sulfonamide;-   N-[2-[3-(Cyclohexylmethyly)-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;-   N-[2-[2-oxo-3-[(3-Phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;-   N-[2-[3-[(2-Amino1,3-thiazol-4-yl)methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;-   N-[2-[3-[(3-Methoxyphenyl)methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;-   N-[2-[3-[(3,4-Difluorophenyl)methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;-   N-[2-[2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]ethyl]benzamide;-   N-[2-[2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]ethyl]benzenesulfonamide;-   3-Methyl-N-[2-[2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]ethyl]butanamide;-   2-Methyl-N-[2-[2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]ethyl]propane-1-sulfonamide;-   N-[3-[2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]propyl]benzamide;-   N-[3-[2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]propyl]benzenesulfonamide;-   3-Methyl-N-[3-[2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]propyl]butanamide;-   2-Methyl-N-[3-[2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]propyl]propane-1-sulfonamide;-   N-[2-[3-[[3-(2-Methoxyethoxy)phenyl]methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;-   N-[2-[2-oxo-5-Phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-1-yl]phenyl]propane-1-sulfonamide;-   N-[2-[2-oxo-5-Phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-1-yl]phenyl]propane-1-sulfonamide;-   N-[2-[2-oxo-3-[[3-(2-Phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;-   N-[2-[3-[[3-(2-Morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;-   N-[2-[2-oxo-3-[[3-[2-oxo-2-(1-Piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;-   N-Methyl-2-[3-[[2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]methyl]phenoxy]acetamide;-   2-[3-[[2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;-   1-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-2-one;-   1-(Cyclohexylmethyly)-3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-3-[(3-phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(2-Amino1,3-thiazol-4-yl)methyl]-3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(3-Methoxyphenyl)methyl]-3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(3,4-Difluorophenyl)methyl]-3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   N-[2-[3-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzamide;-   N-[2-[3-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzenesulfonamide;-   3-Methyl-N-[2-[3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]butanamide;-   2-Methyl-N-[2-[3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]propane-1-sulfonamide;-   N-[3-[3-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzamide;-   N-[3-[3-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzenesulfonamide;-   3-Methyl-N-[3-[3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]butanamide;-   2-Methyl-N-[3-[3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]propane-1-sulfonamide;-   1-[[3-(2-Methoxyethoxy)phenyl]methyl]-3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-2-one;-   1-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-2-one;-   1-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-3-[[3-(2-phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-3-[[3-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-3-[[3-[2-oxo-2-(1-piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   N-Methyl-2-[3-[[3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]acetamide;-   2-[3-[[3-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;-   1-[(2R)-2-Hydroxycyclohexyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-2-one;-   1-(Cyclohexylmethyly)-3-[(2R)-2-hydroxycyclohexyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(2R)-2-Hydroxycyclohexyl]-3-[(3-phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(2-Amino1,3-thiazol-4-yl)methyl]-3-[(2R)-2-hydroxycyclohexyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(2R)-2-Hydroxycyclohexyl]-3-[(3-methoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(3,4-Difluorophenyl)methyl]-3-[(2R)-2-hydroxycyclohexyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;-   N-[2-[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzamide;-   N-[2-[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzenesulfonamide;-   N-[2-[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-3-methyl-butanamide;-   N-[2-[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-2-methyl-propane-1-sulfonamide;-   N-[3-[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzamide;-   N-[3-[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzenesulfonamide;-   N-[3-[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-3-methyl-butanamide;-   N-[3-[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-2-methyl-propane-1-sulfonamide;-   1-[(2R)-2-Hydroxycyclohexyl]-3-[[3-(2-methoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(2R)-2-Hydroxycyclohexyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-2-one;-   1-[(2R)-2-Hydroxycyclohexyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-2-one;-   1-[(2R)-2-Hydroxycyclohexyl]-3-[[3-(2-phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(2R)-2-Hydroxycyclohexyl]-3-[[3-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   1-[(2R)-2-Hydroxycyclohexyl]-3-[[3-[2-oxo-2-(1-piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;-   2-[3-[[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-methyl-acetamide;    and-   2-[3-[[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide.

It is noted that the compounds of the present invention may be in theform of a pharmaceutically acceptable salt. It is further note that thecompounds of the present invention may be in a mixture of stereoisomers,or the compound may comprise a single stereoisomer.

In another of its aspects, the present invention also directs topharmaceutical compositions comprising as an active ingredient acompound according to any one of the preceding embodiments andvariations. In one variation, the pharmaceutical composition is a solidformulation adapted for oral administration. In another variation, thepharmaceutical composition is a liquid formulation adapted for oraladministration. In yet another variation, the pharmaceutical compositionis a tablet. In still another variation, the pharmaceutical compositionis a liquid formulation adapted for parenteral administration.

In yet another variation, the pharmaceutical composition is adapted foradministration by a route selected from the group consisting of orally,parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, and intrathecally.

In yet another of its aspects, the invention is directed to kitscomprising a compound of any one of the above embodiments and variationsand instructions which comprise one or more forms of informationselected from the group consisting of indicating a disease state forwhich the composition is to be administered, storage information for thecomposition, dosing information and instructions regarding how toadminister the composition. In one variation, the kit comprises thecompound in a multiple dose form.

In still another of its aspects, the invention is directed to an articleof manufacture comprising a compound of any one of the above embodimentsand variations; and packaging materials. In one variation, the packagingmaterial comprises a container for housing the compound. In anothervariation, the container comprises a label indicating one or moremembers of the group consisting of a disease state for which thecompound is to be administered, storage information, dosing informationand/or instructions regarding how to administer the compound. In anothervariation, the article of manufacture comprises the compound in amultiple dose form.

In a further of its aspects, the invention is directed to a therapeuticmethod which comprises administering a compound of any one of the aboveembodiments and variations to a subject. In one embodiment, the subjectis an animal. In another embodiment, the subject is a human.

In a further of its aspects, the invention is directed to a method forinhibiting renin. In one embodiment, the method comprises contactingrenin with a compound of any one of the above embodiments andvariations. In another embodiment, the method comprises causing acompound of any one of the above embodiments and variations to bepresent in a subject in order to inhibit renin in vivo. In yet anotherembodiment, the method comprises administering a first compound to asubject that is converted in vivo to a second compound wherein thesecond compound inhibits renin in vivo, the second compound being acompound according to any one of the above embodiments and variations.In one variation, the subject is an animal. In another variation, thesubject is a human.

In yet another of its aspects, the invention is directed to a method fortreating a disease state for which renin possesses activity thatcontributes to the pathology and/or symptomology of the disease state.In one embodiment, the method comprises causing a compound of any one ofthe above embodiments and variations to be present in a subject in atherapeutically effective amount for the disease state. In anotherembodiment, the method comprises administering a compound of any one ofthe above embodiments and variations to a subject, wherein the compoundis present in the subject in a therapeutically effective amount for thedisease state. In yet another embodiment, the method comprisesadministering a first compound to a subject that is converted in vivo toa second compound wherein the second compound inhibits renin in vivo,the second compound being a compound according to any one of the aboveembodiments and variations. It is noted that the disease state cited inthe preceding embodiment and variations, is selected from the groupconsisting of cardiovascular disease, hypertension, congestive heartfailure, myocardial infarction, renal protection, inflammation,neurological disease and cancer.

In another of its aspects, the invention is directed to methods for thepreparation of the inhibitors of the invention. In one embodiment, themethod comprises:

reacting a compound having the formula

with a metalated compound of the formula

under conditions that form a compound of the formula

deprotecting the compound formed above under conditions to yield acompound having the formula

wherein

C^(a) denotes a carbon atom;

N^(a) denotes a nitrogen atom;

PG is a protecting group;

L is a linker moiety between 1-5 atoms in length as measured betweenC^(a) and N^(a);

M is lithium or magnesium halide;

W is selected from the group consisting of alkoxy, aryloxy, fluoro,chloro, and bromo;

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₄alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

R₇ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, carboxamidoalkyl, amidoalkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, or R₇ and asubstituent of L are taken together to form a ring;

provided that R₁ and R₃ are not both hydrogen.

In another embodiment, the method comprises:

coupling an R₂-substituted compound having the formula

to a metalated compound having the formula

under conditions to form a compound having the formula

deprotecting the compound formed above under conditions to yield acompound having the formula

wherein

C^(a) denotes a carbon atom;

N^(a) denotes a nitrogen atom;

PG is a protecting group;

L is a linker moiety between 1-5 atoms in length as measured betweenC^(a) and N^(a);

M is lithium or magnesium halide;

W is selected from the group consisting of alkoxy, aryloxy, fluoro,chloro, and bromo;

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₄alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₂ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

R₇ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, carboxamidoalkyl, amidoalkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, or R₇ and asubstituent of L are taken together to form a ring;

provided that R₁ and R₃ are not both hydrogen.

In another embodiment, the method comprises:

coupling a halide compound having the formula R₂-halide to a compoundhaving the formula

under conditions to form the R₂-substituted compound having the formula

wherein

C^(a) denotes a carbon atom;

W is selected from the group consisting of alkoxy, aryloxy, fluoro,chloro, and bromo;

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₄alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₂ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

provided that R₁ and R₃ are not both hydrogen.

In another embodiment, the method comprises:

converting a compound having the formula

under conditions to produce the metalated compound having the formula

wherein

N^(a) denotes a nitrogen atom;

PG is a protecting group;

Hal is fluoro, chloro or bromo;

L is a linker moiety between 1-5 atoms in length as measured betweenC^(a) and N^(a); and

R₇ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, carboxamidoalkyl, amidoalkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, or R₇ and asubstituent of L are taken together to form a ring.

In one variation of the preceding embodiments and variations of themethod of the invention, when present, M is Li and Hal is Br.

In another variation of the preceding embodiments and variations, W whenpresent is ethoxy and PG is t-butoxycarbonyl (Boc).

In another variation, L is -(A)_(k);

wherein

k is selected from the group consisting of 1, 2, 3, 4 and 5;

each A is independently selected from the group consisting of —NR₉—,—O—, —S—, and —CR₅R₆—,

-   -   where        -   R₅ and R₆ are each independently selected from the group            consisting of hydrogen, oxycarbonyl, sulfonyl, sulfinyl,            (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,            thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,            sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,            hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,            hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,            (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each            substituted or unsubstituted, and R₆ may be absent when the            carbon to which it is bound forms part of a double bond, and            R₅ and R₆ on a given carbon may be taken together to form            ═O, ═S, or ═NR₁₀, wherein R₁₀ is selected from the group            consisting of hydrogen, hydroxyl, alkoxy, aryloxy,            heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₄alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl,            each substituted or unsubstituted,        -   R₉ is selected from the group consisting of hydrogen,            alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl,            halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, aminocarbonylalkyl,            thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,            sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,            alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,            hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,            hetero(C₄₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,            (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each            substituted or unsubstituted, and R₉ may be absent when the            nitrogen to which it is attached forms part of a double            bond, and        -   any two adjacent R₅, R₆, R₇ and R₉ may be taken together to            form a substituted or unsubstituted five, six, seven or            eight membered ring.

In another variation, L is *—NR₉-(A)_(k′)-, wherein

* indicated the point of attachment of —NR₉-(A)_(k′) to M;

k′ is selected from the group consisting of 1, 2, 3 and 4; and

each A is independently selected from the group consisting of —NR₉—,—O—, —S—, and —CR₅R₆—,

-   -   where        -   R₅ and R₆ are each independently selected from the group            consisting of hydrogen, oxycarbonyl, sulfonyl, sulfinyl,            (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,            thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,            sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,            hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,            hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,            (C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each            substituted or unsubstituted, and R₆ may be absent when the            carbon to which it is bound forms part of a double bond, and            R₅ and R₆ on a given carbon may be taken together to form            ═O, ═S, or ═NR₁₀, wherein R₁₀ is selected from the group            consisting of hydrogen, hydroxyl, alkoxy, aryloxy,            heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,            (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₄alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl,            each substituted or unsubstituted.        -   R₉ is selected from the group consisting of hydrogen,            alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl,            halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, aminocarbonylalkyl,            thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,            sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,            alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,            hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,            heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,            hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,            hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,            hetero(C₄₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,            (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each            substituted or unsubstituted, and R₉ may be absent when the            nitrogen to which it is attached forms part of a double            bond, and        -   any two adjacent R₅, R₆, R₇ and R₉ may be taken together to            form a substituted or unsubstituted five, six, seven or            eight membered ring.

In another variation, L is *—NR₉—(CR₅R₆)_(k′)—, wherein

* indicates the point of attachment of —NR₉—(CR₅R₆)_(k′)— to M;

k′ is 1, 2, 3, or 4;

R₅ and R₆ are each independently selected from the group consisting ofhydrogen, oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₆ maybe absent when the carbon to which it is bound forms part of a doublebond, and R₅ and R₆ on a given carbon may be taken together to form ═O,═S, or ═NR₁₀, where R₁₀ is selected from the group consisting ofhydrogen, hydroxyl, alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,(C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl, each substituted or unsubstituted;

R₉ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,aminocarbonylalkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₄₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₉ maybe absent when the nitrogen to which it is attached forms part of adouble bond; and

any two adjacent R₅, R₆, R₇ and R₉ may be taken together to form asubstituted or unsubstituted five, six, seven or eight membered ring.

In another variation, -L-N^(a)R₇PG is selected from the group consistingof

where

k is 0, 1, 2, 3, 4 or 5;

n is 0, 1 or 2;

p is 0, 1, 2, 3 or 4;

N^(a) denotes a nitrogen atom;

PG is a protected group;

each R₄ is independently selected from the group consisting of hydrogen,oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl, alkoxy, oxycarbonyl,aminocarbonyl, amino, amido, carboxamido, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl, alkoxyalkyl, alkylthioalkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,carboxamido(C₁₋₄₀)alkyl, amido(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

R₅ and R₆ are each independently selected from the group consisting ofhydrogen, oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₅ andR₆ on a given carbon may be taken together to form ═O, ═S, or ═NR₁₀,where R₁₀ is selected from the group consisting of hydrogen, hydroxyl,alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl, eachsubstituted or unsubstituted, and R₆ is absent when the carbon to whichit is bound forms part of a double bond;

R₇ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, carboxamidoalkyl, amidoalkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, or R₇ and asubstituent of L are taken together to form a ring, and

R₉ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,aminocarbonylalkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₄₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another embodiment, the method comprises:

coupling a compound having the formula

to a compound having the formula

under conditions that form a compound of the formula

deprotecting the compound formed above under conditions that yield acompound of the formula

wherein

C^(a) denotes a carbon atom;

N^(a) denotes a nitrogen atom;

LG is a leaving group;

PG is a protecting group;

k′ is selected from the group consisting of 1, 2, 3 and 4;

each A is independently selected from the group consisting of —NR₉—,—O—, —S—, and —CR₅R₆—;

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂) aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₅ and R₆ are each independently selected from the group consisting ofhydrogen, oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₆ maybe absent when the carbon to which it is bound forms part of a doublebond, and R₅ and R₆ on a given carbon may be taken together to form ═O,═S, or ═NR₁₀, wherein R₁₀ is selected from the group consisting ofhydrogen, hydroxyl, alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,(C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl, each substituted or unsubstituted;

R₇ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, carboxamidoalkyl, amidoalkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₉ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,aminocarbonylalkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₄₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₉ maybe absent when the nitrogen to which it is attached forms part of adouble bond; and

any two adjacent R₅, R₆, R₇ and R₉ may be taken together to form asubstituted or unsubstituted five, six, seven or eight membered ring;

provided that R₁ and R₃ are not both hydrogen.

In another embodiment, the method comprises:

coupling a compound having the formula

to a compound having the formula

under conditions to form a compound having the formula

deprotecting the compound formed above to yield a compound having theformula

wherein

C^(a) denotes a carbon atom;

N^(a) denotes a nitrogen atom;

LG is a leaving group;

PG is a protecting group;

k′ is selected from the group consisting of 1, 2, 3 and 4;

each A is independently selected from the group consisting of —NR₉—,—O—, —S—, and —CR₅R₆—;

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfonyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₄alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₂ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₅ and R₆ are each independently selected from the group consisting ofhydrogen, oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₆ maybe absent when the carbon to which it is bound forms part of a doublebond, and R₅ and R₆ on a given carbon may be taken together to form ═O,═S, or ═NR₁₀, wherein R₁₀ is selected from the group consisting ofhydrogen, hydroxyl, alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,(C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl, each substituted or unsubstituted;

R₇ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, carboxamidoalkyl, amidoalkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₉ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,aminocarbonylalkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₄₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₉ maybe absent when the nitrogen to which it is attached forms part of adouble bond; and

any two adjacent R₅, R₆, R₇ and R₉ may be taken together to form asubstituted or unsubstituted five, six, seven or eight membered ring;

provided that R₁ and R₃ are not both hydrogen.

In another embodiment, the method comprises:

coupling a compound having the formula

to a compound having the formula

under conditions that form a compound of the formula

deprotecting the compound formed immediately above to form a compoundhaving the formula

wherein

C^(a) denotes a carbon atom;

N^(a) denotes a nitrogen atom;

LG is a leaving group;

PG is a protecting group;

p is 0, 1, 2, 3 or 4;

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₄)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

each R₄ is independently selected from the group consisting of hydrogen,oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl, alkoxy, oxycarbonyl,aminocarbonyl, amino, amido, carboxamido, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl, alkoxyalkyl, alkylthioalkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,carboxamido(C₁₋₄₀)alkyl, amido(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

provided that R₁ and R₃ are not both hydrogen.

In another embodiment, the method comprises:

coupling a compound having the formula

to a compound having the formula

under conditions that form a compound having the formula

coupling a halide compound having the formula R₂-halide to the compoundformed above to form a compound having the formula

deprotecting the compound formed above to yield a compound having theformula

wherein

C^(a) denotes a carbon atom;

N^(a) denotes a nitrogen atom;

LG is a leaving group;

PG is a protecting group;

p is 0, 1, 2, 3 or 4;

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₂ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

each R₄ is independently selected from the group consisting of hydrogen,oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl, alkoxy, oxycarbonyl,aminocarbonyl, amino, amido, carboxamido, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl, alkoxyalkyl, alkylthioalkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,carboxamido(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

provided that R₁ and R₃ are not both hydrogen.

In another embodiment, the method comprises:

reacting a compound having the formula

with a reagent selected from the group consisting of P₂S₅ and Lawesson'sreagent under conditions to form a compound having the formula

deprotecting the compound formed above under conditions to yield acompound having the formula

wherein

C^(a) denotes a carbon atom;

N^(a) denotes a nitrogen atom;

PG is a protecting group;

k′ is selected from the group consisting of 1, 2, 3 and 4;

each A is independently selected from the group consisting of —NR₉—,—O—, —S—, and —CR₅R₆—;

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₄alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₂ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂) aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₅ and R₆ are each independently selected from the group consisting ofhydrogen, oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₆ maybe absent when the carbon to which it is bound forms part of a doublebond, and R₅ and R₆ on a given carbon may be taken together to form ═O,═S, or ═NR₁₀, wherein R₁₀ is selected from the group consisting ofhydrogen, hydroxyl, alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,(C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl, each substituted or unsubstituted;

R₇ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, carboxamidoalkyl, amidoalkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,

R₉ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,aminocarbonylalkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₄₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₉ maybe absent when the nitrogen to which it is attached forms part of adouble bond; and

any two adjacent R₅, R₆, R₇ and R₉ may be taken together to form asubstituted or unsubstituted five, six, seven or eight membered ring;

provided that R₁ and R₃ are not both hydrogen.

In one variation of the preceding embodiments, —NR₉-(A)_(k′)-N^(a)R₇PGwhen present is selected from the group consisting of

where

k is 0, 1, 2, 3, 4 or 5;

n is 0, 1 or 2;

p is 0, 1, 2, 3 or 4;

N^(a) denotes a nitrogen atom;

PG is a protective group;

each R₄ is independently selected from the group consisting of hydrogen,oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl, alkoxy, oxycarbonyl,aminocarbonyl, amino, amido, carboxamido, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl, alkoxyalkyl, alkylthioalkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,carboxamido(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

R₅ and R₆ are each independently selected from the group consisting ofhydrogen, oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₅ andR₆ on a given carbon may be taken together to form ═O, ═S, or ═NR₁₀,where R₁₀ is selected from the group consisting of hydrogen, hydroxyl,alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl, eachsubstituted or unsubstituted, and R₆ is absent when the carbon to whichit is bound forms part of a double bond;

R₇ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, carboxamidoalkyl, amidoalkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

R₉ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,aminocarbonylalkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₄₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₉ maybe absent when the nitrogen to which it is attached forms part of adouble bond.

In another embodiment, the method further comprises:

reacting a primary urea having the formula

with a diazo compound having the formula

under conditions to form an insertion product having the formula

cyclizing the insertion product forming an imidazolone ester having theformula

wherein

C^(a) denotes a carbon atom;

R_(a) is alkyl;

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₄alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

provided that R₁ and R₃ are not both hydrogen.

In another embodiment, the method further comprises:

reacting a dicarbonyl compound having the formula

with an aryl sulfonylazide compound having the formula

under conditions that form a diazo compound having the formula

wherein

C^(a) denotes a carbon atom;

R_(a) is alkyl; and

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfonyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₄alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another embodiment, the method further comprises:

reacting a amine compound having the formula NH₂—R₃ with potassiumcyanate under the conditions to yield the primary urea having theformula

wherein

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another embodiment, the method further comprises:

converting a nitro derivative of R₃ having the formula NO₂—R₃ underreaction conditions to form the amine having the formula NH₂—R₃.

In another embodiment, the method further comprises:

hydrolyzing an imidazolone ester having the formula

under conditions to form a carboxylic acid having the formula

wherein

C^(a) denotes a carbon atom;

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₄alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

provided that R₁ and R₃ are not both hydrogen.

In another embodiment, the method comprises:

coupling an imidate compound having the formula

to a compound having the formula

under condition to form an amidine having the formula

deprotecting the amidine compound to yield a compound having the formula

wherein

C^(a) denotes a carbon atom;

N^(a) denotes a nitrogen atom;

PG is a protecting group;

k′ is selected from the group consisting of 1, 2, 3 and 4;

each A is independently selected from the group consisting of —NR₉—,—O—, —S—, and —CR₅R₆—;

R_(a) is alkyl;

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₄alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₅ and R₆ are each independently selected from the group consisting ofhydrogen, oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₆ maybe absent when the carbon to which it is bound forms part of a doublebond, and R₅ and R₆ on a given carbon may be taken together to form ═O,═S, or ═NR₁₀, wherein R₁₀ is selected from the group consisting ofhydrogen, hydroxyl, alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,(C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl, each substituted or unsubstituted;

R₇ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, carboxamidoalkyl, amidoalkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₉ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,aminocarbonylalkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₄₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₉ maybe absent when the nitrogen to which it is attached forms part of adouble bond; and

any two adjacent R₅, R₆, R₇ and R₉ may be taken together to form asubstituted or unsubstituted five, six, seven or eight membered ring;

provided that R₁ and R₃ are not both hydrogen.

In the preceding embodiment, the method further comprises:

converting a cyano imidazolone compound having the formula

under conditions to produce the imidate having the formula

In another embodiment, the method comprises:

coupling an imidate compound having the formula

to a compound having the formula

under condition to form an amidine having the formula

deprotecting the amidine compound to form a compound of the inventionhaving the formula

wherein

C^(a) denotes a carbon atom;

N^(a) denotes a nitrogen atom;

PG is a protecting group;

k′ is selected from the group consisting of 1, 2, 3 and 4;

each A is independently selected from the group consisting of —NR₉—,—O—, —S—, and —CR₅R₆—;

R_(a) is alkyl;

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₄alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₂ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂) aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₅ and R₆ are each independently selected from the group consisting ofhydrogen, oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₆ maybe absent when the carbon to which it is bound forms part of a doublebond, and R₅ and R₆ on a given carbon may be taken together to form ═O,═S, or ═NR₁₀, wherein R₁₀ is selected from the group consisting ofhydrogen, hydroxyl, alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl,(C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl, each substituted or unsubstituted;

R₇ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, carboxamidoalkyl, amidoalkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₉ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,aminocarbonylalkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₄₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₉ maybe absent when the nitrogen to which it is attached forms part of adouble bond; and

any two adjacent R₅, R₆, R₇ and R₉ may be taken together to form asubstituted or unsubstituted five, six, seven or eight membered ring;

provided that R₁ and R₃ are not both hydrogen.

In the preceding embodiment, the method further comprises:

coupling a halide compound having the formula R₂-halide to a cyanoimidazolone compound having the formula

under conditions to produce an R₂-substituted cyano imidazolone

converting the R₂-substituted cyano imidazolone compound underconditions to produce an imidate having the formula

wherein

C_(a) denotes a nitrogen atom;

R_(a) is alkyl;

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₄alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₂ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

provided that R₁ and R₃ are not both hydrogen.

In one variation of the preceding embodiments and variations, whenpresent, —NR₉-(A)_(k′)-N^(a)R₇PG is selected from the group consistingof

wherein

k is 0, 1, 2, 3, 4 or 5;

n is 0, 1 or 2;

p is 0, 1, 2, 3 or 4;

N^(a) denotes a nitrogen atom;

PG is a protecting group;

each R₄ is independently selected from the group consisting of hydrogen,oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl, alkoxy, oxycarbonyl,aminocarbonyl, amino, amido, carboxamido, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl, alkoxyalkyl, alkylthioalkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,carboxamido(C₁₋₄₀)alkyl, amido(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

R₅ and R₆ are each independently selected from the group consisting ofhydrogen, oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₅ andR₆ on a given carbon may be taken together to form ═O, ═S, or ═NR₁₀,where R₁₀ is selected from the group consisting of hydrogen, hydroxyl,alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl, eachsubstituted or unsubstituted, and R₆ is absent when the carbon to whichit is bound forms part of a double bond;

R₇ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, carboxamidoalkyl, amidoalkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

R₉ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,aminocarbonylalkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₄₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

provided that R₁ and R₃ are not both hydrogen.

In another embodiment, the method further comprises:

reacting a primary urea having the formula

with a diazo compound having the formula

under conditions to form an insertion product having the formula

cyclizing the insertion product to yield the cyano imidazolone compoundhaving the formula

wherein

C_(a) denotes a nitrogen atom;

R_(a) is alkyl;

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₄alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

provided that R₁ and R₃ are not both hydrogen.

In another embodiment, the method further comprises

reacting a compound having the formula

with an aryl sulfonylazide compound having the formula

under conditions that form a compound having the formula

wherein

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₄alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another embodiment, the method comprising:

coupling a carboxylic acid compound of the formula

to a piperazine of the formula

under conditions that form an intermediate of the formula

coupling the intermediate formed above to R₂-Hal, to form an initialproduct of the formula

and deprotecting the initial product to yield a final product of theformula

wherein

PG is a protecting group;

p is 0, 1, 2, 3 or 4;

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₂ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

each R₄ is independently selected from the group consisting of hydrogen,oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl, alkoxy, oxycarbonyl,aminocarbonyl, amino, amido, carboxamido, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl, alkoxyalkyl, alkylthioalkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,carboxamido(C₁₋₄₀)alkyl, amido(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

provided that R₁ and R₃ are not both hydrogen.

In one variation of the above embodiment, the carboxylic acid compoundis formed by the procedure comprising:

reacting a primary urea having the formula

with a diazo compound having the formula

under conditions to form an insertion product having the formula

cyclizing the insertion product forming an imidazolone ester having theformula

and hydrolyzing the imidazolone ester under conditions to form thecarboxylic acid compound;

where R^(a) is (C₁₋₃)alkyl.

In another variation of the above embodiment, the diazo compound isformed by the procedure comprising:

reacting a dicarbonyl compound having the formula

where R^(a) is (C₁₋₃)alkyl, with an aryl sulfonylazide compound havingthe formula

under conditions that form the diazo compound.

In another variation of the above embodiment, the primary urea is formedby a procedure comprising:

converting NO₂—R₃, a nitro derivative of R₃ under reaction conditions toan amine having the formula NH₂—R₃; and

reacting the amine compound with potassium cyanate under the conditionsto yield the primary urea.

In another embodiment, the method further comprises converting theproduct produced by the various embodiments and variations of the methodinto an acid or base addition salt. In one variation, the acid or baseaddition salt is selected from the group consisting of hydrochloride,trifluoroacetate, formate, acetate, toluenesulfonate, benzenesulfonate,methanesulfonate, oxalate, succinate, tartrate, citrate, lactate,maleate, fumarate, bisulfate, phosphorate, hydrobromate, benzoate,bis-hydrochloride, bis-trifluoroacetate, sulfate,aphthylene-2-sulfonate, propionate, hydroiodate, R-mandelate, andlithium salt, potassium salt, and sodium salt.

In another of its aspects, the invention is directed to reagents whichare useful in the preparation of the compounds of the invention.

In one embodiment, the reagent is a carboxylic compound consisting ofthe formula

wherein

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfonyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

Examples of useful carboxylic acid reagent include, but are not limitedto:

-   2-Oxo-1,5-diphenyl-2,3-dihydro-1H-imidazole-4-carboxylic acid;-   5-(3-Fluorophenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic    acid;-   1-(3-Morpholinophenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic    acid;-   1-(6-Morpholinopyridin-2-yl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic    acid;-   5-Isopropyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic    acid;-   5-Cyclopropyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic    acid;-   5-(Cyclopropylmethyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic    acid;-   5-(2-Chlorophenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic    acid;-   5-(3-Chlorophenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic    acid;-   5-(4-Chlorophenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic    acid;-   1-Cyclohexyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic    acid;-   1-(1-(Benzyloxycarbonyl)piperidin-3-yl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic    acid;-   1-((1R,2R)-2-(Benzyloxy)cyclohexyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic    acid;-   1-(2-(2-Methoxyethoxy)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic    acid;-   1-(2-(3-Methoxypropoxy)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic    acid;-   1-(3-(2-Methoxyethoxy)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic    acid; and-   1-(3-(3-Methoxypropoxy)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylic    acid.

In another embodiment, the reagent is a piperazine compound useful inthe preparation of the compounds of the invention consisting of theformula

wherein

p is 0, 1, 2, 3 or 4;

PG is a protecting group;

each R₄ is independently selected from the group consisting of hydrogen,oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl, alkoxy, oxycarbonyl,aminocarbonyl, amino, amido, carboxamido, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl, alkoxyalkyl, alkylthioalkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,carboxamido(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted.

In another embodiment, the reagent is an imidazolone initial productuseful in the preparation of the compounds of the invention consistingof the formula

wherein

PG is a protecting group;

p is 0, 1, 2, 3 or 4;

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₂ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,amido(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted;

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

each R₄ is independently selected from the group consisting of hydrogen,oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl, alkoxy, oxycarbonyl,aminocarbonyl, amino, amido, carboxamido, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl, alkoxyalkyl, alkylthioalkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,carboxamido(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

provided that R₁ and R₃ are not both hydrogen.

Example of the imidazolone initial product reagent include, but are notlimited to:

-   tert-Butyl    4-(5-cyclopropyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate;-   tert-Butyl    4-(5-(cyclopropylmethyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate;-   tert-Butyl    4-(5-(2-chlorophenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate;-   tert-Butyl    4-(5-(3-chlorophenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate;-   tert-Butyl    4-(5-(4-chlorophenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate;-   tert-Butyl    4-(1-cyclohexyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate;-   tert-Butyl    4-(1-(1-(benzyloxycarbonyl)piperidin-3-yl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate;-   tert-Butyl    4-(1-((1R,2R)-2-(benzyloxy)cyclohexyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate;-   tert-Butyl    4-(1-(2-(2-methoxyethoxy)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate;-   tert-Butyl    4-(1-(2-(3-methoxypropoxy)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate;-   tert-Butyl    4-(1-(3-(2-methoxyethoxy)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate;-   tert-Butyl    4-(1-(3-(3-methoxypropoxy)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate;-   tert-Butyl    4-(1-cyclohexyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)-3-methylpiperazine-1-carboxylate;-   (R)-tert-Butyl    3-benzyl-4-(2-oxo-1,5-diphenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate;-   tert-Butyl    4-(1-cyclohexyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)-2-methylpiperazine-1-carboxylate;-   tert-Butyl    4-(1-cyclohexyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)-2,5-dimethylpiperazine-1-carboxylate;    and-   tert-Butyl    3-(hydroxymethyl)-4-(2-oxo-1,5-diphenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate.

In another embodiment, the reagent useful in the preparation of thefinal product is a diazo compound consisting of the formula

wherein

R₁ is selected from the group consisting of hydrogen, carbonyl,oxycarbonyl, aminocarbonyl, (C₁₋₁₀)alkylamino, sulfonamido, sulfonyl,sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₄alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₂₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

Examples of the diazo compound useful for the production of thecompounds of the invention includes, but are not limited to:

-   Ethyl 2-diazo-3-oxo-3-phenylpropanoate;-   Ethyl 2-diazo-3-(3-fluorophenyl)-3-oxopropanoate;-   Methyl 2-diazo-4-methyl-3-oxopentanoate;-   Ethyl 3-(2-chlorophenyl)-2-diazo-3-oxopropanoate;-   Ethyl 4-cyclopropyl-2-diazo-3-oxobutanoate; and-   Ethyl 3-cyclopropyl-2-diazo-3-oxopropanoate.

In another embodiment, the reagent useful in the preparation of thecompounds of the invention is a primary amine consisting of the formula

wherein

R₃ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, alkoxy(C₁₋₁₀)alkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, carboxamido(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

In another embodiment, the reagent useful in the preparation of thecompounds of the invention is an insertion product consisting of theformula

Examples of useful insertion product reagent include, but are notlimited to:

-   Ethyl 2-oxo-1,5-diphenyl-2,3-dihydro-1H-imidazole-4-carboxylate;-   Ethyl    5-(3-fluorophenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate;-   Ethyl    1-(3-morpholinophenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate;-   Ethyl    1-(6-Morpholinopyridin-2-yl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate;-   Ethyl    5-(3-fluorophenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate;-   Ethyl    5-cyclopropyl-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate;-   Ethyl    5-(cyclopropylmethyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate;-   Ethyl    5-(2-chlorophenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate;-   Ethyl    5-(3-chlorophenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate;-   Ethyl    5-(4-chlorophenyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate;-   Ethyl    1-cyclohexyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate;-   Benzyl    3-(4-(ethoxycarbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate;-   Ethyl    1-((1R,2R)-2-(benzyloxy)cyclohexyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate;-   Ethyl    1-(2-(2-methoxyethoxy)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate;-   Ethyl    1-(2-(3-methoxypropoxy)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate;-   Ethyl    1-(3-(2-methoxyethoxy)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate;    and-   Ethyl    1-(3-(3-methoxypropoxy)phenyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate.

In another embodiment, the reagent is a diamine having a formulaselected from the group consisting of

where

k is 0, 1, 2, 3, 4 or 5;

n is 0, 1 or 2;

p is 0, 1, 2, 3 or 4;

N^(a) denotes a nitrogen atom;

PG is a protecting group;

each R₄ is independently selected from the group consisting of hydrogen,oxo, oxyalkyl, alkoxycarbonyl, carbonyl, thioalkyl, alkoxy, oxycarbonyl,aminocarbonyl, amino, amido, carboxamido, sulfonyl, sulfinyl,(C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, oxyalkyl, alkoxyalkyl, alkylthioalkyl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,carboxamido(C₁₋₄₀)alkyl, amido(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, aryloxyalkyl, heteroarylalkyl,(C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl,(C₃₋₁₂)cycloalkyl, hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,hetero(C₃₋₁₂)bicycloalkyl, (C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl,(C₉₋₁₂)bicycloaryl, and hetero(C₄₋₁₂)bicycloaryl, each substituted orunsubstituted;

R₅ and R₆ are each independently selected from the group consisting ofhydrogen, oxycarbonyl, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl,imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted, and R₅ andR₆ on a given carbon may be taken together to form ═O, ═S, or ═NR₁₀,where R₁₀ is selected from the group consisting of hydrogen, hydroxyl,alkoxy, aryloxy, heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₅₋₁₂)aryl, and hetero(C₂₋₁₀)aryl, eachsubstituted or unsubstituted, and R₆ is absent when the carbon to whichit is bound forms part of a double bond;

R₇ is selected from the group consisting of hydrogen, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, carboxamidoalkyl, amidoalkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl,amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl, alkoxy(C₁₋₃)alkyl,(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl,aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted; and

R₉ is selected from the group consisting of hydrogen, alkoxy, aryloxy,heteroaryloxy, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,aminocarbonylalkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, amino(C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,alkoxy(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₂₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₂₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₄₋₁₂)bicycloalkyl,(C₅₋₁₂)aryl, hetero(C₂₋₁₀)aryl, (C₉₋₁₂)bicycloaryl, andhetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted.

Salts, Hydrates, and Prodrugs of Renin Inhibitors

It should be recognized that the compounds of the present invention maybe present and optionally administered in the form of salts, hydratesand prodrugs that are converted in vivo into the compounds of thepresent invention.

A “pharmaceutically acceptable salt”, as used herein, is intended toencompass any compound according to the present invention that isutilized in the form of a salt thereof, especially where the saltconfers on the compound improved pharmacokinetic properties as comparedto the free form of compound or a different salt form of the compound.The pharmaceutically acceptable salt form may also initially conferdesirable pharmacokinetic properties on the compound that it did notpreviously possess, and may even positively affect the pharmacodynamicsof the compound with respect to its therapeutic activity in the body. Anexample of a pharmacokinetic property that may be favorably affected isthe manner in which the compound is transported across cell membranes,which in turn may directly and positively affect the absorption,distribution, biotransformation and excretion of the compound. While theroute of administration of the pharmaceutical composition is important,and various anatomical, physiological and pathological factors cancritically affect bioavailability, the solubility of the compound isusually dependent upon the character of the particular salt formthereof, which it utilized. One of skill in the art will appreciate thatan aqueous solution of the compound will provide the most rapidabsorption of the compound into the body of a subject being treated,while lipid solutions and suspensions, as well as solid dosage forms,will result in less rapid absorption of the compound.

It is within the scope of the present invention to convert the compoundsof the present invention into and use them in the form of theirpharmaceutically acceptable salts derived from various organic andinorganic acids and bases in accordance with procedures well known inthe art.

When the compounds of the present invention possess a free base form,the compounds can be prepared as a pharmaceutically acceptable acidaddition salt by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, e.g.,hydrohalides such as hydrochloride, hydrobromide, hydroiodide; othermineral acids and their corresponding salts such as sulfate, nitrate,phosphate, etc.; and alkyl and monoarylsulfonates such asethanesulfonate, toluenesulfonate and benzenesulfonate; and otherorganic acids and their corresponding salts such as acetate, tartrate,maleate, succinate, citrate, benzoate, salicylate and ascorbate. Furtheracid addition salts of the present invention include, but are notlimited to: adipate, alginate, arginate, aspartate, bisulfate,bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate,chloride, chlorobenzoate, cyclopentanepropionate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate,galacterate (from mucic acid), galacturonate, glucoheptaoate, gluconate,glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate,hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate,lactobionate, malate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate and phthalate. It should be recognized that the free baseforms will typically differ from their respective salt forms somewhat inphysical properties such as solubility in polar solvents, but otherwisethe salts are equivalent to their respective free base forms for thepurposes of the present invention.

When the compounds of the present invention possess a free acid form, apharmaceutically acceptable base addition salt can be prepared byreacting the free acid form of the compound with a pharmaceuticallyacceptable inorganic or organic base. Examples of such bases are alkalimetal hydroxides including potassium, sodium and lithium hydroxides;alkaline earth metal hydroxides such as barium and calcium hydroxides;alkali metal alkoxides, e.g., potassium ethanolate and sodiumpropanolate; and various organic bases such as ammonium hydroxide,piperidine, diethanolamine and N-methylglutamine. Also included are thealuminum salts of the compounds of the present invention. Further basesalts of the present invention include, but are not limited to: copper,ferric, ferrous, lithium, magnesium, manganic, manganous, potassium,sodium and zinc salts. Organic base salts include, but are not limitedto, salts of primary, secondary and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, e.g., arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, iso-propylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris-(hydroxymethyl)-methylamine(tromethamine). It should be recognized that the free acid forms willtypically differ from their respective salt forms somewhat in physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid forms for the purposes ofthe present invention.

Compounds of the present invention that comprise basicnitrogen-containing groups may be quaternized with such agents as(C₁₋₄)alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butylchlorides, bromides and iodides; di(C₁₋₄)alkyl sulfates, e.g., dimethyl,diethyl and diamyl sulfates; (C₁₀₋₁₈)alkyl halides, e.g., decyl,dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides;and aryl(C₁₋₄)alkyl halides, e.g., benzyl chloride and phenethylbromide. Such salts permit the preparation of both water-soluble andoil-soluble compounds of the present invention.

Compounds of the invention further include prodrug derivatives of thecompounds. It is noted that in many instances, the prodrugs themselvesalso fall within the scope of the range of compounds according to thepresent invention.

Various forms of prodrugs are well known in the art. For examples ofsuch prodrug derivatives, see, e.g.,

-   a) Design of Prodrugs, Bundgaard, A. Ed., Elsevier, 1985 and Method    in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p.    309-396;-   b) Bundgaard, H. “Design and Application of Prodrugs” in A Textbook    of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard,    Ed., 1991, Chapter 5, p. 113-191; and-   c) Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38.    Each of which is incorporated herein by reference.

Pharmaceutically acceptable prodrugs of the compounds of this inventioninclude, but are not limited to, esters, carbonates, thiocarbonates,N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivativesof tertiary amines, N-Mannich bases, Schiff bases, amino acidconjugates, phosphate esters, metal salts and sulfonate esters.

Compounds of the present invention may also be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compositions Comprising Renin Inhibitors

A wide variety of compositions and administration methods may be used inconjunction with the compounds of the present invention. Suchcompositions may include, in addition to the compounds of the presentinvention, conventional pharmaceutical excipients, and otherconventional, pharmaceutically inactive agents. Additionally, thecompositions may include active agents in addition to the compounds ofthe present invention. These additional active agents may includeadditional compounds according to the invention, and/or one or moreother pharmaceutically active agents.

The compositions may be in gaseous, liquid, semi-liquid or solid form,formulated in a manner suitable for the route of administration to beused. For oral administration, capsules and tablets are typically used.For parenteral administration, reconstitution of a lyophilized powder,prepared as described herein, is typically used.

Compositions comprising compounds of the present invention may beadministered or coadministered orally, parenterally, intraperitoneally,intravenously, intraarterially, transdermally, sublingually,intramuscularly, rectally, transbuccally, intranasally, liposomally, viainhalation, vaginally, intraoccularly, via local delivery (for exampleby catheter or stent), subcutaneously, intraadiposally,intraarticularly, or intrathecally. The compounds and/or compositionsaccording to the invention may also be administered or coadministered inslow release dosage forms.

The renin inhibitors and compositions comprising them may beadministered or coadministered in any conventional dosage form.Co-administration in the context of this invention is intended to meanthe administration of more than one therapeutic agent, one of whichincludes a renin inhibitor, in the course of a coordinated treatment toachieve an improved clinical outcome. Such co-administration may also becoextensive, that is, occurring during overlapping periods of time.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application may optionally include one or more of thefollowing components: a sterile diluent, such as water for injection,saline solution, fixed oil, polyethylene glycol, glycerine, propyleneglycol or other synthetic solvent; antimicrobial agents, such as benzylalcohol and methyl parabens; antioxidants, such as ascorbic acid andsodium bisulfite; chelating agents, such as ethylenediaminetetraaceticacid (EDTA); buffers, such as acetates, citrates and phosphates; agentsfor the adjustment of tonicity such as sodium chloride or dextrose, andagents for adjusting the acidity or alkalinity of the composition, suchas alkaline or acidifying agents or buffers like carbonates,bicarbonates, phosphates, hydrochloric acid, and organic acids likeacetic and citric acid. Parenteral preparations may optionally beenclosed in ampules, disposable syringes or single or multiple dosevials made of glass, plastic or other suitable material.

When compounds according to the present invention exhibit insufficientsolubility, methods for solubilizing the compounds may be used. Suchmethods are known to those of skill in this art, and include, but arenot limited to, using cosolvents, such as dimethylsulfoxide (DMSO),using surfactants, such as TWEEN, or dissolution in aqueous sodiumbicarbonate. Derivatives of the compounds, such as prodrugs of thecompounds may also be used in formulating effective pharmaceuticalcompositions.

Upon mixing or adding compounds according to the present invention to acomposition, a solution, suspension, emulsion or the like may be formed.The form of the resulting composition will depend upon a number offactors, including the intended mode of administration, and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration needed to ameliorate the disease being treatedmay be empirically determined.

Compositions according to the present invention are optionally providedfor administration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, dry powders for inhalers, granules,sterile parenteral solutions or suspensions, and oral solutions orsuspensions, and oil-water emulsions containing suitable quantities ofthe compounds, particularly the pharmaceutically acceptable salts,preferably the sodium salts, thereof. The pharmaceuticallytherapeutically active compounds and derivatives thereof are typicallyformulated and administered in unit-dosage forms or multiple-dosageforms. Unit-dose forms, as used herein, refers to physically discreteunits suitable for human and animal subjects and packaged individuallyas is known in the art. Each unit-dose contains a predetermined quantityof the therapeutically active compound sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier, vehicle or diluent. Examples of unit-dose forms includeampoules and syringes individually packaged tablet or capsule. Unit-doseforms may be administered in fractions or multiples thereof. Amultiple-dose form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pint or gallons. Hence, multipledose form is a multiple of unit-doses that are not segregated inpackaging.

In addition to one or more compounds according to the present invention,the composition may comprise: a diluent such as lactose, sucrose,dicalcium phosphate, or carboxymethylcellulose; a lubricant, such asmagnesium stearate, calcium stearate and talc; and a binder such asstarch, natural gums, such as gum acaciagelatin, glucose, molasses,polyinylpyrrolidine, celluloses and derivatives thereof, povidone,crospovidones and other such binders known to those of skill in the art.Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, or otherwise mixing an activecompound as defined above and optional pharmaceutical adjuvants in acarrier, such as, for example, water, saline, aqueous dextrose,glycerol, glycols, ethanol, and the like, to form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of auxiliary substances suchas wetting agents, emulsifying agents, or solubilizing agents, pHbuffering agents and the like, for example, acetate, sodium citrate,cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodiumacetate, triethanolamine oleate, and other such agents. Actual methodsof preparing such dosage forms are known in the art, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15thEdition, 1975. The composition or formulation to be administered will,in any event, contain a sufficient quantity of a inhibitor of thepresent invention to reduce renin activity in vivo, thereby treating thedisease state of the subject.

Dosage forms or compositions may optionally comprise one or morecompounds according to the present invention in the range of 0.005% to100% (weight/weight) with the balance comprising additional substancessuch as those described herein. For oral administration, apharmaceutically acceptable composition may optionally comprise any oneor more commonly employed excipients, such as, for examplepharmaceutical grades of mannitol, lactose, starch, magnesium stearate,talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose,magnesium carbonate, sodium saccharin, talcum. Such compositions includesolutions, suspensions, tablets, capsules, powders, dry powders forinhalers and sustained release formulations, such as, but not limitedto, implants and microencapsulated delivery systems, and biodegradable,biocompatible polymers, such as collagen, ethylene vinyl acetate,polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid andothers. Methods for preparing these formulations are known to thoseskilled in the art. The compositions may optionally contain 0.01%-100%(weight/weight) of one or more renin inhibitors, optionally 0.1-95%, andoptionally 1-95%.

Salts, preferably sodium salts, of the inhibitors may be prepared withcarriers that protect the compound against rapid elimination from thebody, such as time release formulations or coatings. The formulationsmay further include other active compounds to obtain desiredcombinations of properties.

Formulations for Oral Administration

Oral pharmaceutical dosage forms may be as a solid, gel or liquid.Examples of solid dosage forms include, but are not limited to tablets,capsules, granules, and bulk powders. More specific examples of oraltablets include compressed, chewable lozenges and tablets that may beenteric-coated, sugar-coated or film-coated. Examples of capsulesinclude hard or soft gelatin capsules. Granules and powders may beprovided in non-effervescent or effervescent forms. Each may be combinedwith other ingredients known to those skilled in the art.

In certain embodiments, compounds according to the present invention areprovided as solid dosage forms, preferably capsules or tablets. Thetablets, pills, capsules, troches and the like may optionally containone or more of the following ingredients, or compounds of a similarnature: a binder; a diluent; a disintegrating agent; a lubricant; aglidant; a sweetening agent; and a flavoring agent.

Examples of binders that may be used include, but are not limited to,microcrystalline cellulose, gum tragacanth, glucose solution, acaciamucilage, gelatin solution, sucrose and starch paste.

Examples of lubricants that may be used include, but are not limited to,talc, starch, magnesium or calcium stearate, lycopodium and stearicacid.

Examples of diluents that may be used include, but are not limited to,lactose, sucrose, starch, kaolin, salt, mannitol and dicalciumphosphate.

Examples of glidants that may be used include, but are not limited to,colloidal silicon dioxide.

Examples of disintegrating agents that may be used include, but are notlimited to, crosscarmellose sodium, sodium starch glycolate, alginicacid, corn starch, potato starch, bentonite, methylcellulose, agar andcarboxymethylcellulose.

Examples of coloring agents that may be used include, but are notlimited to, any of the approved certified water-soluble FD and C dyes,mixtures thereof; and water insoluble FD and C dyes suspended on aluminahydrate.

Examples of sweetening agents that may be used include, but are notlimited to, sucrose, lactose, mannitol and artificial sweetening agentssuch as sodium cyclamate and saccharin, and any number of spray-driedflavors.

Examples of flavoring agents that may be used include, but are notlimited to, natural flavors extracted from plants such as fruits andsynthetic blends of compounds that produce a pleasant sensation, suchas, but not limited to peppermint and methyl salicylate.

Examples of wetting agents that may be used include, but are not limitedto, propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate and polyoxyethylene lauryl ether.

Examples of anti-emetic coatings that may be used include, but are notlimited to, fatty acids, fats, waxes, shellac, ammoniated shellac andcellulose acetate phthalates.

Examples of film coatings that may be used include, but are not limitedto, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the salt of the compound mayoptionally be provided in a composition that protects it from the acidicenvironment of the stomach. For example, the composition can beformulated in an enteric coating that maintains its integrity in thestomach and releases the active compound in the intestine. Thecomposition may also be formulated in combination with an antacid orother such ingredient.

When the dosage unit form is a capsule, it may optionally additionallycomprise a liquid carrier such as a fatty oil. In addition, dosage unitforms may optionally additionally comprise various other materials thatmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents.

Compounds according to the present invention may also be administered asa component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may optionally comprise, in addition to theactive compounds, sucrose as a sweetening agent and certainpreservatives, dyes and colorings and flavors.

The compounds of the present invention may also be mixed with otheractive materials that do not impair the desired action, or withmaterials that supplement the desired action, such as antacids, H₂blockers, and diuretics. For example, if a compound is used for treatingasthma or hypertension, it may be used with other bronchodilators andantihypertensive agents, respectively.

Examples of pharmaceutically acceptable carriers that may be included intablets comprising compounds of the present invention include, but arenot limited to binders, lubricants, diluents, disintegrating agents,coloring agents, flavoring agents, and wetting agents. Enteric-coatedtablets, because of the enteric-coating, resist the action of stomachacid and dissolve or disintegrate in the neutral or alkaline intestines.Sugar-coated tablets may be compressed tablets to which different layersof pharmaceutically acceptable substances are applied. Film-coatedtablets may be compressed tablets that have been coated with polymers orother suitable coating. Multiple compressed tablets may be compressedtablets made by more than one compression cycle utilizing thepharmaceutically acceptable substances previously mentioned. Coloringagents may also be used in tablets. Flavoring and sweetening agents maybe used in tablets, and are especially useful in the formation ofchewable tablets and lozenges.

Examples of liquid oral dosage forms that may be used include, but arenot limited to, aqueous solutions, emulsions, suspensions, solutionsand/or suspensions reconstituted from non-effervescent granules andeffervescent preparations reconstituted from effervescent granules.

Examples of aqueous solutions that may be used include, but are notlimited to, elixirs and syrups. As used herein, elixirs refer to clear,sweetened, hydroalcoholic preparations. Examples of pharmaceuticallyacceptable carriers that may be used in elixirs include, but are notlimited to solvents. Particular examples of solvents that may be usedinclude glycerin, sorbitol, ethyl alcohol and syrup. As used herein,syrups refer to concentrated aqueous solutions of a sugar, for example,sucrose. Syrups may optionally further comprise a preservative.

Emulsions refer to two-phase systems in which one liquid is dispersed inthe form of small globules throughout another liquid. Emulsions mayoptionally be oil-in-water or water-in-oil emulsions. Examples ofpharmaceutically acceptable carriers that may be used in emulsionsinclude, but are not limited to non-aqueous liquids, emulsifying agentsand preservatives.

Examples of pharmaceutically acceptable substances that may be used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents.

Examples of pharmaceutically acceptable substances that may be used ineffervescent granules, to be reconstituted into a liquid oral dosageform, include organic acids and a source of carbon dioxide.

Coloring and flavoring agents may optionally be used in all of the abovedosage forms.

Particular examples of preservatives that may be used include glycerin,methyl and propylparaben, benzoic add, sodium benzoate and alcohol.

Particular examples of non-aqueous liquids that may be used in emulsionsinclude mineral oil and cottonseed oil.

Particular examples of emulsifying agents that may be used includegelatin, acacia, tragacanth, bentonite, and surfactants such aspolyoxyethylene sorbitan monooleate.

Particular examples of suspending agents that may be used include sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluentsinclude lactose and sucrose. Sweetening agents include sucrose, syrups,glycerin and artificial sweetening agents such as sodium cyclamate andsaccharin.

Particular examples of wetting agents that may be used include propyleneglycol monostearate, sorbitan monooleate, diethylene glycol monolaurateand polyoxyethylene lauryl ether.

Particular examples of organic acids that may be used include citric andtartaric acid.

Sources of carbon dioxide that may be used in effervescent compositionsinclude sodium bicarbonate and sodium carbonate. Coloring agents includeany of the approved certified water soluble FD and C dyes, and mixturesthereof.

Particular examples of flavoring agents that may be used include naturalflavors extracted from plants such fruits, and synthetic blends ofcompounds that produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is preferablyencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g.,for example, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g., water,to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. Re 28,819 and4,358,603.

Injectables, Solutions, and Emulsions

The present invention is also directed to compositions designed toadminister the compounds of the present invention by parenteraladministration, generally characterized by subcutaneous, intramuscularor intravenous injection. Injectables may be prepared in anyconventional form, for example as liquid solutions or suspensions, solidforms suitable for solution or suspension in liquid prior to injection,or as emulsions.

Examples of excipients that may be used in conjunction with injectablesaccording to the present invention include, but are not limited towater, saline, dextrose, glycerol or ethanol. The injectablecompositions may also optionally comprise minor amounts of non-toxicauxiliary substances such as wetting or emulsifying agents, pH bufferingagents, stabilizers, solubility enhancers, and other such agents, suchas for example, sodium acetate, sorbitan monolaurate, triethanolamineoleate and cyclodextrins. Implantation of a slow-release orsustained-release system, such that a constant level of dosage ismaintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplatedherein. The percentage of active compound contained in such parenteralcompositions is highly dependent on the specific nature thereof, as wellas the activity of the compound and the needs of the subject.

Parenteral administration of the formulations includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as the lyophilized powders describedherein, ready to be combined with a solvent just prior to use, includinghypodermic tablets, sterile suspensions ready for injection, sterile dryinsoluble products ready to be combined with a vehicle just prior to useand sterile emulsions. The solutions may be either aqueous ornonaqueous.

When administered intravenously, examples of suitable carriers include,but are not limited to physiological saline or phosphate buffered saline(PBS), and solutions containing thickening and solubilizing agents, suchas glucose, polyethylene glycol, and polypropylene glycol and mixturesthereof.

Examples of pharmaceutically acceptable carriers that may optionally beused in parenteral preparations include, but are not limited to aqueousvehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents,buffers, antioxidants, local anesthetics, suspending and dispersingagents, emulsifying agents, sequestering or chelating agents and otherpharmaceutically acceptable substances.

Examples of aqueous vehicles that may optionally be used include SodiumChloride Injection, Ringers Injection, Isotonic Dextrose Injection,Sterile Water Injection, Dextrose and Lactated Ringers Injection.

Examples of nonaqueous parenteral vehicles that may optionally be usedinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil.

Antimicrobial agents in bacteriostatic or fungistatic concentrations maybe added to parenteral preparations, particularly when the preparationsare packaged in multiple-dose containers and thus designed to be storedand multiple aliquots to be removed. Examples of antimicrobial agentsthat may be used include phenols or cresols, mercurials, benzyl alcohol,chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters,thimerosal, benzalkonium chloride and benzethonium chloride.

Examples of isotonic agents that may be used include sodium chloride anddextrose. Examples of buffers that may be used include phosphate andcitrate. Examples of antioxidants that may be used include sodiumbisulfate. Examples of local anesthetics that may be used includeprocaine hydrochloride. Examples of suspending and dispersing agentsthat may be used include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Examples of emulsifying agentsthat may be used include Polysorbate 80 (TWEEN 80). Sequestering orchelating agents of metal ions include EDTA.

Pharmaceutical carriers may also optionally include ethyl alcohol,polyethylene glycol and propylene glycol for water miscible vehicles andsodium hydroxide, hydrochloric acid, citric acid or lactic acid for pHadjustment.

The concentration of an inhibitor in the parenteral formulation may beadjusted so that an injection administers a pharmaceutically effectiveamount sufficient to produce the desired pharmacological effect. Theexact concentration of an inhibitor and/or dosage to be used willultimately depend on the age, weight and condition of the patient oranimal as is known in the art.

Unit-dose parenteral preparations may be packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration should be sterile, as is know and practiced in the art.

Injectables may be designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,preferably more than 1% w/w of the renin inhibitor to the treatedtissue(s). The inhibitor may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment willbe a function of the location of where the composition is parenterallyadministered, the carrier and other variables that may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test data. It is to be noted that concentrations anddosage values may also vary with the age of the individual treated. Itis to be further understood that for any particular subject, specificdosage regimens may need to be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the formulations.Hence, the concentration ranges set forth herein are intended to beexemplary and are not intended to limit the scope or practice of theclaimed formulations.

The renin inhibitor may optionally be suspended in micronized or othersuitable form or may be derivatized to produce a more soluble activeproduct or to produce a prodrug. The form of the resulting mixturedepends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease state and may be empiricallydetermined.

Lyophilized Powders

The compounds of the present invention may also be prepared aslyophilized powders, which can be reconstituted for administration assolutions, emulsions and other mixtures. The lyophilized powders mayalso be formulated as solids or gels.

Sterile, lyophilized powder may be prepared by dissolving the compoundin a sodium phosphate buffer solution containing dextrose or othersuitable excipient. Subsequent sterile filtration of the solutionfollowed by lyophilization under standard conditions known to those ofskill in the art provides the desired formulation. Briefly, thelyophilized powder may optionally be prepared by dissolving dextrose,sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose orother suitable agent, about 1-20%, preferably about 5 to 15%, in asuitable buffer, such as citrate, sodium or potassium phosphate or othersuch buffer known to those of skill in the art at, typically, aboutneutral pH. Then, a renin inhibitor is added to the resulting mixture,preferably above room temperature, more preferably at about 30-35° C.,and stirred until it dissolves. The resulting mixture is diluted byadding more buffer to a desired concentration. The resulting mixture issterile filtered or treated to remove particulates and to insuresterility, and apportioned into vials for lyophilization. Each vial maycontain a single dosage or multiple dosages of the inhibitor.

Topical Administration

The compounds of the present invention may also be administered astopical mixtures. Topical mixtures may be used for local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The renin inhibitors may be formulated as aerosols for topicalapplication, such as by inhalation (see, U.S. Pat. Nos. 4,044,126,4,414,209, and 4,364,923, which describe aerosols for delivery of asteroid useful for treatment of inflammatory diseases, particularlyasthma). These formulations for administration to the respiratory tractcan be in the form of an aerosol or solution for a nebulizer, or as amicrofine powder for insufflation, alone or in combination with an inertcarrier such as lactose. In such a case, the particles of theformulation will typically have diameters of less than 50 microns,preferably less than 10 microns.

The inhibitors may also be formulated for local or topical application,such as for topical application to the skin and mucous membranes, suchas in the eye, in the form of gels, creams, and lotions and forapplication to the eye or for intracisternal or intraspinal application.Topical administration is contemplated for transdermal delivery and alsofor administration to the eyes or mucosa, or for inhalation therapies.Nasal solutions of the renin inhibitor alone or in combination withother pharmaceutically acceptable excipients can also be administered.

Formulations for Other Routes of Administrations

Depending upon the disease state being treated, other routes ofadministration, such as topical application, transdermal patches, andrectal administration, may also be used. For example, pharmaceuticaldosage forms for rectal administration are rectal suppositories,capsules and tablets for systemic effect. Rectal suppositories are usedherein mean solid bodies for insertion into the rectum that melt orsoften at body temperature releasing one or more pharmacologically ortherapeutically active ingredients. Pharmaceutically acceptablesubstances utilized in rectal suppositories are bases or vehicles andagents to raise the melting point. Examples of bases include cocoabutter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethyleneglycol) and appropriate mixtures of mono-, di- and triglycerides offatty acids. Combinations of the various bases may be used. Agents toraise the melting point of suppositories include spermaceti and wax.Rectal suppositories may be prepared either by the compressed method orby molding. The typical weight of a rectal suppository is about 2 to 3gm. Tablets and capsules for rectal administration may be manufacturedusing the same pharmaceutically acceptable substance and by the samemethods as for formulations for oral administration.

Examples of Formulations

The following are particular examples of oral, intravenous and tabletformulations that may optionally be used with compounds of the presentinvention. It is noted that these formulations may be varied dependingon the particular compound being used and the indication for which theformulation is going to be used.

Oral Formulation

Compound of the Present Invention 10-100 mg Citric Acid Monohydrate 105mg Sodium Hydroxide 18 mg Flavoring Water q.s. to 100 mL

Intravenous Formulation

Compound of the Present Invention 0.1-10 mg Dextrose Monohydrate q.s. tomake isotonic Citric Acid Monohydrate 1.05 mg Sodium Hydroxide 0.18 mgWater for Injection q.s. to 1.0 mL

Tablet Formulation

Compound of the Present Invention  1% Microcrystalline Cellulose 73%Stearic Acid 25% Colloidal Silica  1%.Kits Comprising Renin Inhibitors

The invention is also directed to kits and other articles of manufacturefor treating diseases associated with Renin. It is noted that diseasesare intended to cover all conditions for which the renin possessactivity that contributes to the pathology and/or symptomology of thecondition.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one inhibitor of the present invention incombination with instructions. The instructions may indicate the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one inhibitor of the presentinvention in combination with packaging materials. The packagingmaterial may comprise a container for housing the composition. Thecontainer may optionally comprise a label indicating the disease statefor which the composition is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition. The kit may also optionally comprise additional components,such as syringes for administration of the composition. The kit maycomprise the composition in single or multiple dose forms.

It is noted that the packaging material used in kits and articles ofmanufacture according to the present invention may form a plurality ofdivided containers such as a divided bottle or a divided foil packet.The container can be in any conventional shape or form as known in theart which is made of a pharmaceutically acceptable material, for examplea paper or cardboard box, a glass or plastic bottle or jar, are-sealable bag (for example, to hold a “refill” of tablets forplacement into a different container), or a blister pack with individualdoses for pressing out of the pack according to a therapeutic schedule.The container that is employed will depend on the exact dosage forminvolved, for example a conventional cardboard box would not generallybe used to hold a liquid suspension. It is feasible that more than onecontainer can be used together in a single package to market a singledosage form. For example, tablets may be contained in a bottle that isin turn contained within a box. Typically the kit includes directionsfor the administration of the separate components. The kit form isparticularly advantageous when the separate components are preferablyadministered in different dosage forms (e.g., oral, topical, transdermaland parenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

One particular example of a kit according to the present invention is aso-called blister pack. Blister packs are well known in the packagingindustry and are being widely used for the packaging of pharmaceuticalunit dosage forms (tablets, capsules, and the like). Blister packsgenerally consist of a sheet of relatively stiff material covered with afoil of a preferably transparent plastic material. During the packagingprocess recesses are formed in the plastic foil. The recesses have thesize and shape of individual tablets or capsules to be packed or mayhave the size and shape to accommodate multiple tablets and/or capsulesto be packed. Next, the tablets or capsules are placed in the recessesaccordingly and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are individually sealed or collectively sealed, as desired, inthe recesses between the plastic foil and the sheet. Preferably thestrength of the sheet is such that the tablets or capsules can beremoved from the blister pack by manually applying pressure on therecesses whereby an opening is formed in the sheet at the place of therecess. The tablet or capsule can then be removed via said opening.

Another specific embodiment of a kit is a dispenser designed to dispensethe daily doses one at a time in the order of their intended use.Preferably, the dispenser is equipped with a memory-aid, so as tofurther facilitate compliance with the regimen. An example of such amemory-aid is a mechanical counter that indicates the number of dailydoses that has been dispensed. Another example of such a memory-aid is abattery-powered micro-chip memory coupled with a liquid crystal readout,or audible reminder signal which, for example, reads out the date thatthe last daily dose has been taken and/or reminds one when the next doseis to be taken.

Combination Therapy

A wide variety of therapeutic agents may have a therapeutic additive orsynergistic effect with renin inhibitors according to the presentinvention. Such therapeutic agents may additively or synergisticallycombine with the renin inhibitors to reduce or alleviate the effects andsymptoms of cardiovascular disease.

In one embodiment, a method is provided for treating cardiovasculardisease comprising treating cells with a compound according to thepresent invention in combination with an aldosterone receptorantagonist, wherein the cells are treated with the compound according tothe present invention before, at the same time, and/or after the cellsare treated with the aldosterone receptor antagonist, referred to hereinas combination therapy. It is noted that treatment of one agent beforeanother is referred to herein as sequential therapy, even if the agentsare also administered together. It is noted that combination therapy isintended to cover when agents are administered before or after eachother (sequential therapy) as well as when the agents are administeredat the same time.

Preparation of Renin Inhibitors

Various methods may be developed for synthesizing compounds according tothe present invention. General schemes for synthesizing these compoundsare provided below and exemplified in the Examples. It is noted,however, that the compounds of the present invention may also besynthesized by other synthetic routes that others may devise.

It will be readily recognized that certain compounds according to thepresent invention have atoms with linkages to other atoms that confer aparticular stereochemistry to the compound (e.g., chiral centers). It isrecognized that synthesis of compounds according to the presentinvention may result in the creation of mixtures of differentstereoisomers (i.e., enantiomers and diastereomers). Unless a particularstereochemistry is specified, recitation of a compound is intended toencompass all of the different possible stereoisomers.

Various methods for separating mixtures of different stereoisomers areknown in the art. For example, a racemic mixture of a compound may bereacted with an optically active resolving agent to form a pair ofdiastereoisomeric compounds. The diastereomers may then be separated inorder to recover the optically pure enantiomers. Dissociable complexesmay also be used to resolve enantiomers (e.g., crystallinediastereoisomeric salts). Diastereomers typically have sufficientlydistinct physical properties (e.g., melting points, boiling points,solubilities, reactivity, etc.) and can be readily separated by takingadvantage of these dissimilarities. For example, diastereomers cantypically be separated by chromatography or by separation/resolutiontechniques based upon differences in solubility. A more detaileddescription of techniques that can be used to resolve stereoisomers ofcompounds from their racemic mixture can be found in Jean Jacques AndreCollet and Samuel H. Wilen, Enantiomers, Racemates and Resolutions, JohnWiley & Sons, Inc. (1981).

Compounds according to the present invention can also be prepared as apharmaceutically acceptable acid addition salt by reacting the free baseform of the compound with a pharmaceutically acceptable inorganic ororganic acid. Alternatively, a pharmaceutically acceptable base additionsalt of a compound can be prepared by reacting the free acid form of thecompound with a pharmaceutically acceptable inorganic or organic base.Inorganic and organic acids and bases suitable for the preparation ofthe pharmaceutically acceptable salts of compounds are set forth in thedefinitions section of this Application. Alternatively, the salt formsof the compounds can be prepared using salts of the starting materialsor intermediates.

The free acid or free base forms of the compounds can be prepared fromthe corresponding base addition salt or acid addition salt form. Forexample, a compound in an acid addition salt form can be converted tothe corresponding free base by treating with a suitable base (e.g.,ammonium hydroxide solution, sodium hydroxide, and the like). A compoundin a base addition salt form can be converted to the corresponding freeacid by treating with a suitable acid (e.g., hydrochloric acid, etc).

The N-oxides of compounds according to the present invention can beprepared by methods known to those of ordinary skill in the art. Forexample, N-oxides can be prepared by treating an unoxidized form of thecompound with an oxidizing agent (e.g., trifluoroperacetic acid,permaleic acid, perbenzoic acid, peracetic acid,meta-chloroperoxybenzoic acid, or the like) in a suitable inert organicsolvent (e.g., a halogenated hydrocarbon such as dichloromethane) atapproximately 0° C. Alternatively, the N-oxides of the compounds can beprepared from the N-oxide of an appropriate starting material.

Compounds in an unoxidized form can be prepared from N-oxides ofcompounds by treating with a reducing agent (e.g., sulfur, sulfurdioxide, triphenyl phosphine, lithium borohydride, sodium borohydride,phosphorus trichloride, tribromide, or the like) in an suitable inertorganic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or thelike) at 0 to 80° C.

Prodrug derivatives of the compounds can be prepared by methods known tothose of ordinary skill in the art. For example, appropriate prodrugscan be prepared by reacting a non-derivatized compound with a suitablecarbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate,para-nitrophenyl carbonate, or the like) or an acylating agent. Furtherexamples of methods of making prodrugs are described in Saulnier et al.Bioorganic and Medicinal Chemistry Letters, 1994, Vol. 4, p. 1985. Thoseof ordinary skill in the art have the knowledge and means to accomplishthis without undue experimentation.

Protected derivatives of the compounds can be made by methods known tothose of ordinary skill in the art. A detailed description of thetechniques applicable to the creation of protecting groups and theirremoval can be found in T. W. Greene, Protecting Groups in OrganicSynthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

Compounds according to the present invention may be convenientlyprepared or formed during the process of the invention, as solvates(e.g., hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds according to the present invention can also be prepared astheir individual stereoisomers by reacting a racemic mixture of thecompound with an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomer. While resolution of enantiomers can becarried out using covalent diastereomeric derivatives of compounds,dissociable complexes are preferred (e.g., crystalline diastereoisomericsalts). Diastereomers have distinct physical properties (e.g., meltingpoints, boiling points, solubilities, reactivity, etc.) and can bereadily separated by taking advantage of these dissimilarities. Thediastereomers can be separated by chromatography or, preferably, byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques Andre Collet and Samuel H. Wilen,Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

μL (microliters) Ac (acetyl) atm (atmosphere) ATP (AdenosineTriphophatase) BOC (tert-butyloxycarbonyl) BOP(bis(2-oxo-3-oxazolidinyl)phosphinic chloride) Brij35(polyoxyethyleneglycol BSA (Bovine Serum Albumin) dodecylether) CBZ(benzyloxycarbonyl) CDI (1,1-carbonyldiimidazole) DCC(dicyclohexylcarbodiimide) DCE (dichloroethane) DCM (dichloromethane)DMAP (4-dimethylaminopyridine) DME (1,2-dimethoxyethane) DMF(N,N-dimethylformamide) DMPU (N,N′-dimethylpropyleneurea) DMSO(dimethylsulfoxide) DTT (dithiothreitol) EDCI (ethylcarbodiimidehydrochloride) EDTA (Ethylenediaminetetraacetic acid) Et (ethyl) Et₂O(diethyl ether) EtOAc (ethyl acetate) FMOC (9-fluorenylmethoxycarbonyl)g (grams) h (hours) HOAc or AcOH (acetic acid) HOBT(1-hydroxybenzotriazole) HOSu (N-hydroxysuccinimide) HPLC (high pressureliquid Hz (Hertz) chromatography) i.v. (intravenous) IBCF (isobutylchloroformate) i-PrOH (isopropanol) L (liters) LAH (lithium aluminumhydride) M (molar) mCPBA (meta-chloroperbenzoic acid) Me (methyl) MeOH(methanol) mg (milligrams) MHz (megahertz) min (minutes) mL(milliliters) mM (millimolar) mmol (millimoles) mol (moles) MOPS(Morpholinepropanesulfonic acid) mp (melting point) NaOAc (sodiumacetate) NEt₃ (triethylamine) OMe (methoxy) OTf (O-triflate) OMs(O-mesylate) psi (pounds per square inch) RP (reverse phase) RT (ambienttemperature) SPA (Scintillation Proximity Assay) TBAF(tetra-n-butylammonium fluoride) TBS (t-butyldimethylsilyl) tBu(tert-butyl) TEA (triethylamine) TFA (trifluoroacetic acid) TFAA(trifluoroacetic anhydride) THF (tetrahydrofuran) TIPS(triisopropylsilyl) TLC (thin layer chromatography) TMS (trimethylsilyl)TMSE (2-(trimethylsilyl)ethyl) Tr (retention time)

All references to ether or Et₂O are to diethyl ether; and brine refersto a saturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsare conducted under an inert atmosphere at RT unless otherwise noted.

¹H NMR spectra were recorded on a Bruker Avance 400. Chemical shifts areexpressed in parts per million (ppm). Coupling constants are in units ofHertz (Hz). Splitting patterns describe apparent multiplicities and aredesignated as s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), br (broad). When two rotomers are observed, the combinedNMR spectra are presented.

Low-resolution mass spectra (MS) and compound purity data were acquiredon a Waters ZQ LC/MS single quadrupole system equipped with electrosprayionization (ESI) source, UV detector (220 and 254 nm), and evaporativelight scattering detector (ELSD). Thin-layer chromatography wasperformed on 0.25 mm E. Merck silica gel plates (60F-254), visualizedwith UV light, 5% ethanolic phosphomolybdic acid, Ninhydrin orp-anisaldehyde solution. Flash column chromatography was performed onsilica gel (230-400 mesh, Merck).

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as the AldrichChemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma(St. Louis, Mo.), or may be prepared by methods well known to a personof ordinary skill in the art, following procedures described in suchstandard references as Fieser and Fieser's Reagents for OrganicSynthesis, vols. 1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd'sChemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier SciencePublishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons,New York, N.Y., 1991; March J.: Advanced Organic Chemistry, 4th ed.,John Wiley and Sons, New York, N.Y.; and Larock: Comprehensive OrganicTransformations, VCH Publishers, New York, 1989.

The entire disclosures of all documents cited throughout thisapplication are incorporated herein by reference.

A. Synthetic Schemes for Compounds of the Present Invention

Compounds according to the present invention may be synthesizedaccording to the reaction schemes shown below. Other reaction schemescould be readily devised by those skilled in the art. It should also beappreciated that a variety of different solvents, temperatures and otherreaction conditions can be varied to optimize the yields of thereactions.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee T. W. Greene and P. G. M. Wuts in Protective Groups in OrganicChemistry, John Wiley and Sons, 1991.

In describing the general synthetic routes for producing compounds ofthe present invention, the definitions of the various substituents areeither specifically provided or they are the same as taught throughoutthe disclosure.

Scheme 1 provides a general procedure for the N—H insertion reaction ofprimary ureas with diazo compounds and the conversion of these productsinto imidazolones and ultimately into imidazolone ketones of theinvention.

A dicarbonyl compound such as 3-carbonylacetate 1A may be treated withan aryl sulfonylazide 1B in the presence of a base such as triethylamineto give a diazocarbonyl compound 1C (Step 1). The diazocarbonyl compound1C may be reacted with a primary urea 1D in the presence of a rhodiumcatalyst, such as rhodium (II) octanoate or rhodium (II) acetate, in asolvents such as a 1:1 mixture of 1,2-dichloroethane and toluene atelevated temperature (e.g., 80° C.) to yield an insertion product 1E(Step 2). In most cases, the insertion product 1E is formed very rapidlyand the reaction can be completed within 1 hr of heating at 80° C. Incases where the urea 1D is sparingly soluble in the solvent mixture, itmay be necessary to break down the urea into fine powder by grinding ofthe solid urea and/or sonicating the mixture prior to the reaction;otherwise, lower yield or slower reaction may result.

The insertion product 1E may be cyclized to the correspondingimidazolone ester 1F in the presence of an acid for example,trifluoroacetic acid (Step 3). The acid may be added to the reactionmixture directly; or in some instances, the solvent may be removed invacuo first and the remaining residue can then be treated withtrifluoroacetic acid to effect the formation of the imidazolone ester1F. In some instances, heating the reaction mixture in TFA may also benecessary. The imidazolone ester 1F may be isolated by columnchromatography from the concentrated crude product.

Imidazolone ester 1F may be N-alkylated under a basic condition (such asNaH in DMF) with an alkylating reagent 1J to give an alkylatedimidazolone ester 1K (Step 4).

The imidazolone ester 1F or 1K may be treated with excess organolithiumterminal amine reagent 1M (or Grignard reagent) to provide thecorresponding imidazolone ketone 1G or 1N, respectively (Step 6).Typically, the reaction was carried out at temperature ranging from −78°C. to room temperature using solvents such as THF or ether. The reagentIM may be obtained by reaction of the corresponding protected terminalamine halide 1L with butyllithium or isopropylmagnesium bromide (Step5).

The protected compound 1G or 1N can be deprotected by appropriatereagents to provide the desired imidazolone ketone renin inhibitors 1Hor 1O, respectively. TFA may be used for the removal of a Boc group, andPd-catalyzed hydrogenolysis may be used for the removal of a Bn group(Step 7).

The preparation of a diazocarbonyl 2C from the treatment of acarbonylacetate 2A with aryl sulfonylazide 2B, its reaction with aprimary ureas 2D to form an insertion product 2E, and the cyclization ofthe insert product 2E to the corresponding imidazolone ester 2F mayproceed as described in Scheme 1, Steps 1-3.

The imidazolone ester 2F may be isolated by column chromatography fromthe concentrated crude product first and then hydrolyzed into thecorresponding acid 2G (Step 4); or in some cases, the imidazolone ester2F may be hydrolysized directly to the corresponding acid 2G.

The acid 2G may be purified and coupled with a diamine derivative 2H toprovide the amide product 2I. The diamine derivatives 2H are typicallymonoprotected on one of the nitrogens by a protecting group such as aBoc or Bn group; however, unprotected piperazines such as 2,5-dimethylpiperazine can also be used directly for the coupling reaction.

The protected amide product 2I can be deprotected by appropriatereagents to provide the desired renin inhibitor 2J; TFA may be used forthe removal of a Boc group, and Pd-catalyzed hydrogenolysis may be usedfor the removal of a Bn group (Step 6).

Further, the protected amide product 2I may be N-alkylated under a basiccondition (such as NaH in DMF) with an alkylating reagent 2K (Step 7) togive a protect product 2L (Step 7), which upon deprotection (Step 8) togive the desired renin inhibitor 2M.

Ureas used in the insertion reaction (Scheme 1, step 2) that are notcommercially available may be prepared by the reaction of KNCO with anamine in the presence of an acid, e.g., acetic acid.

An amine 3A (20 mmol) may be first mixed with KCNO (1 equivalent) in 24mL of water, and the mixture chilled to 0° C. prior to the addition ofan acid, such as glacial acetic acid (1.17 mL, 1 equivalent). Thetemperature of the reaction mixture may be allowed to rise to roomtemperature, and the corresponding ureas 3B may precipitate in about 2hours. The reaction may be allowed to continue overnight while stirringat room temperature. The solid may be filtered; rinsed with water anddried under vacuum to provide primary ureas 3B.

Amines may be prepared from the corresponding nitro derivatives in areduction reaction by SnCl₂ dihydrate. Alternatively, the reaction maybe catalyzed by Pd/C under a hydrogen atmosphere.

A nitro derivative 4A (˜12 mmol) may be mixed in with tin chloridedihydrate (13.36 g, 5 equivalents) in 25 mL of ethyl acetate and heatedat 60° C. for about two hours and then chilled at 0° C. Triethylamine(25-30 mL) may be added slowly until a white precipitate is formed. Thewhite precipitate may be removed by filteration over a Celite plug. Thefiltrate may be washed with brine, dried over MgSO₄, and thenconcentrated and dried under vacuum to provide the amine derivative 4B.

An imidazolone nitrile 5F can be synthesized using the same procedure asthat described for the synthesis of imidazolone ester 1F (Scheme 1,Steps 1-3). Alkylation of 5F with R₂—X using similar procedure as thatfor conversion of 1F to 1K (Scheme 1, Step 4) to give an N-alkylatednitrile 5F.

The nitrile or N-alkylated nitrile 5F may be converted to thecorresponding imidate 5G upon the treatment with HCl (Step 4). HCl gasmay be bubbled through a solution of 2-imidazolone nitrile 5F (2 mmol)in anhydrous EtOH (5 mL) at 0° C. for 2 to 10 mins. The resultingmixture may be allowed to react for 2-72 hrs while stirring at roomtemperature. The imidate may be precipitate with ether, and theresulting precipitates collected by filtration (under nitrogen) orcentrifugation, rinsed with ether and dried to give the desired imidates5G as HCl salt.

Imidates may be reacted with amines (e.g., monoprotected piperazine) toyield protected products (Step 5). To a stirred solution of an imidate5G (0.05 mmol) in anhydrous EtOH (200 μl) may be added mono-protectedamine 5H (0.06 mmol) and diisopropylethylamine (0.15 mmol). Theresulting mixture may be stirred for 1 to 24 h at room temperature.After removal of solvent under reduced pressure, the crude product maybe purified by RP-HPLC to give the 2-imidazolone amidine 5I.Deprotection of 5I according to the procedure described in Scheme 2,Step 6 will give corresponding amidine product 5J (Step 6).

Imidazolone thioamides 6A or 6B may be prepared from imidazolones 2I or2L (Scheme 2), respectively, by the reaction with Lawesson reagent orP₂O₅.

Lawesson reagent or P₂O₅ may be added to a solution of amide 2I or 2L intoluene (or dioxane). The resulting mixture may be stirred at roomtemperature or heated (up to reflux) for 2 hr to 48 hrs. After removalof the solvent under reduced pressure, the crude product may be purifiedby RP-HPLC to give the N-protected 2-imidazolone thioamide, which upondeprotection with an acid (e.g., TFA) to give the desired thioamide 6Aor 6B.

It is understood that in each of the above reaction procedures orschemes, the various substituents may be selected from the varioussubstituents taught herein.

Chiral components can be separated and purified using any of a varietyof techniques known to those skilled in the art. For example, chiralcomponents can be purified using supercritical fluid chromatography(SFC). In one particular variation, chiral analytical SFC/MS analysesare conducted using a Berger analytical SFC system (AutoChem, Newark,Del.) which consists of a Berger SFC dual pump fluid control module witha Berger FCM 1100/1200 supercritical fluid pump and FCM 1200 modifierfluid pump, a Berger TCM 2000 oven, and an Alcott 718 autosampler. Theintegrated system can be controlled by BI-SFC Chemstation softwareversion 3.4. Detection can be accomplished with a Waters ZQ 2000detector operated in positive mode with an ESI interface and a scanrange from 200-800 Da with 0.5 second per scan. Chromatographicseparations can be performed on a ChiralPak AD-H, ChiralPak AS-H,ChiralCel OD-H, or ChiralCel OJ-H column (5μ, 4.6×250 mm; ChiralTechnologies, Inc. West Chester, Pa.) with 10 to 40% methanol as themodifier and with or without ammonium acetate (10 mM). Any of a varietyof flow rates can be utilized including, for example, 1.5 or 3.5 mL/minwith an inlet pressure set at about 100 bar. Additionally, a variety ofsample injection conditions can be used including, for example, sampleinjections of either 5 or 10 μL in methanol at 0.1 mg/mL inconcentration.

In another variation, preparative chiral separations are performed usinga Berger MultiGram II SFC purification system. For example, samples canbe loaded onto a ChiralPak AD column (21×250 mm, 10μ). In particularvariations, the flow rate for separation can be 70 mL/min, the injectionvolume up to 2 mL, and the inlet pressure set at 130 bar. Stackedinjections can be applied to increase the efficiency.

The present invention is further exemplified, but not limited, byexamples provided in the EXAMPLE section below that describe thesynthesis of particular compounds according to the invention.

Biological Testing

The activity of compounds as renin inhibitors may be assayed in vitro,in vivo or in a cell line. Example D below provides an in vitroenzymatic activity assay for activity against Renin.

Test compounds in varying concentrations may be reacted with recombinanthuman renin in the presence of a substrate, e.g.,QXL520-γ-Abu-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-Lys(HiLyteFluo488)-Arg-OH (Anaspec, San Jose, Calif.). The reaction can befollowed kinetically using fluorescence (excitation λ=485 nm; emissionλ=538 nm). Inhibition constants (IC₅₀) may be calculated by non-linearcurve fitting of the compound concentrations and fluorescenceintensities to the standard IC₅₀ equation. IC₅₀ values for selectedcompounds of the present invention are given in Table 1.

EXAMPLE General Procedures for the Preparation of Imidazolone Amides ofthe Invention

A. General Procedure for Diazo Transfer (Scheme A, Step 1)

To a solution of the β-ketoester substrate A1 (10 mmol) and4-acetamidobenzenesulfonyl azide A2 (11 mmol) in ethyl acetate (60 mL)at 0° C. is added triethylamine (30 mmol) dropwise. After stirring atroom temperature for 16 h, the reaction mixture is concentrated in vacuoand the resultant solid is triturated with ether-light petroleum. Thefiltrate is concentrated in vacuo and purified by flash chromatographyon silica gel eluting with ethyl acetate-light petroleum (1:4) to yieldthe desired product A3.

B. General Procedure for Rhodium-Catalyzed N—H Insertion Reaction(Scheme A, Step 2)

To a vigorously stirred and heated (80° C.) suspension of R₁-diazocompound A3 (2 mmol) and a finely powdered primary urea A4 (1.5 eq), forexample phenyl urea in toluene-1,2-dichloroethane (1:1, 20 mL), asuspension of Rh₂Oct₄ (31 mg, 0.04 mmol) in toluene (4 mL) is added over10 min. After addition of the catalyst, the mixture is stirred for anadditional 60 min to 24 hrs to give the corresponding insertion productA5.

C. General Procedure for TFA-Promoted Cyclization Reaction (Scheme A,Step 3)

To the cooled insertion reaction mixture A5 is added TFA (1 mL), and theresulting solution is stirred for 1 h at room temperature.Alternatively, the insertion mixture A5 is evaporated, and then treatedwith neat TFA (10 mL) for 3 h to 24 h at 50 to 90° C. After removal ofsolvent under reduced pressure, the residue is purified by flashchromatography to give corresponding 2-imidazolone ester A6.

D. Hydrolysis of 2-Imidazolones Carboxyl Esters (Scheme A, Step 4)

To a stirred mixture of 2-imidazolone ester A6 (1 mmol) in dioxane/EtOH(9 mL, 7:2) is added 5 eq of NaOH in 1 mL water (5 mmol) at roomtemperature under nitrogen, and the resulting suspension was stirred for3 to 24 h at 50-80° C. After removal of solvent under reduced pressure,the crude product, 2-imidazolone acid, A7, is either used directly forthe amide coupling reaction or purified by RP-HPLC.

E. Amide Coupling of 2-Imidazolones Carboxyl Acid (Scheme A, Step 5)

To a stirred mixture of 2-imidazolone acid A7 (1 mmol) and EDCI in DCMor DMF (5 mL) was added 1.2 eq of the a mono-protected amine A8 in 2-5mL of DCM or DMF (1.2 mmol) at 0° C. under nitrogen;diisopropylethylamine (3 mmol, 3 eq) was then added and the resultingsuspension was stirred for 24 h at room temperature. After removal ofsolvent under reduced pressure, the crude product is purified by RP-HPLCto give the 2-imidazolone amide A9.

F. Alkylation at the N-3 Position of 2-Imidazolones and De-Protection,(Scheme A, Steps 6, 7 and 8)

To a stirred mixture of 2-imidazolone amide A9 (0.2 mmol) in DMF (2 mL)is added 1.2 eq of 60% NaH at room temperature under nitrogen. Theresulting suspension is stirred for 30 min at room temperature, and analkyl halide All is added either neat or as a solution in DMF (1 mL).The mixture is stirred at room temperature or heated to 50-100° C. for 1to 24 hrs. The solvent is removed under reduced pressure to providecompound A12.

The Boc protected group of compounds A9 and A12 may be removed bystirring with 20% TFA-DCM for 30 mins to 24 hrs at room temperature. Thesolvent is then removed under reduced pressure, and the crude productsis purified by RP-HPLC to afford analytically pure, imidazolones A10 andA13.

General Procedure for the Preparation of Alkyloxyalkyloxyphenyl Urea

Alkyloxyalkyloxyphenyl ureas may be prepared from nitrophenols via thethree-step reaction route (Scheme B) above.

A solution of a nitrophenol B1 (2.0 g, 14.377 mmol) in anhydrous DMF (5mL) is added slowly to a solution of sodium hydride (95%, 0.4141 g,17.253 mmol) in anhydrous DMF (50 mL) that has been stirring at 0° C.under nitrogen for about 10 minutes. To the mixture, a solution of a1-bromo-alkyoxyalkane B2 (1.1 eq) in anhydrous DMF (5 mL) is addeddropwise. The reaction mixture is then allowed to reach room temperatureand stirred for about 18 hours under nitrogen. The reaction is quenchedin water, and the product extracted into organic solvent such as ethylacetate. The organic layer is washed with brine, dried over MgSO₄, andconcentrated in vacuo to give alkyoxyalkoxynitrobenzene B3 as an amberoil (Step 1).

The alkyoxyalkoxynitrobenzene B3 (11.84 mmol) is combined with tinchloride dihydrate (5 eq) in ethyl acetate (25 mL). The mixture isheated at 60° C. for about two hours and then chilled at 0° C.Triethylamine (25-30 mL) is added slowly until a white precipitate isformed; the white precipitate is removed by filtration. The filtrate iswashed with brine then dried over MgSO₄. The aniline B4 is collected byconcentrating the filtrate in vacuo and dried under vacuum (Step 2).Alternatively, the aniline B4 is prepared from B3 by a reductionreaction catalyzed by Pd/C in a hydrogen atmosphere.

To a flask containing the aniline B4 (2.00 g, 11.04 mmol) is charged a100 mL solution of 80% glacial acetic acid and 20% water; the mixture ischilled to 0° C. A solution of potassium cyanate (1.5 eq) in 5 mL ofwater is slowly added portion-wise to the reaction mixture. The glacialacetic acid is removed under reduced pressure after the reaction mixturehas been stirred for about 1 hour at RT. The resulting white solidresidue is collected by filtration and rinsed with copious amounts ofwater then dried under vacuum to give the urea B5 (Step 3).

Example 1 Ethyl 2-diazo-3-oxo-3-phenylpropanoate

The title compound was prepared according to Scheme A, Step 1, and wasobtained as a yellow oil (83%). ESI-MS: m/z 219.3 (M+H)⁺.

Other compounds prepared by Scheme A, Step 1:

Name Structure MS Ethyl 2-diazo-3-(3-fluorophenyl)-3 - oxopropanoate

ESI-MS: m/z 237.3 (M + H)⁺. Methyl 2-diazo-4-methyl-3- oxopentanoate

ESI-MS: m/z 171.1 (M + H)⁺. Ethyl 3-(2-chlorophenyl)-2-diazo-3-oxopropanoate

ESI-MS: m/z 253.10 (M + H)⁺. Ethyl 4-cyclopropyl-2-diazo-3- oxobutanoate

ESI- MS: m/z 197.10 (M + H)⁺. Ethyl 3-cyclopropyl-2-diazo-3-oxopropanoate

ESI- MS: m/z 183.10 (M + H)⁺.

Example 2 Ethyl2-oxo-1,5-diphenyl-2,3-dihydro-1H-imidazole-4-carboxylate

The title compound was prepared according to Scheme A, Steps 1-3, andwas obtained as a yellow oil (83%) ESI-MS: m/z 309.3 (M+H)⁺.

Other compounds prepared by Scheme A, Steps 1-3:

Structure/MS

Example 3 2-Oxo-1,5-diphenyl-2,3-dihydro-1H-imidazole-4-carboxylic acid

The title compound was prepared according to Scheme A, Steps 1-4 and wasobtained as a yellow oil (90%). ESI-MS: m/z 281.1 (M+H)⁺.

Other compounds prepared by Scheme A, Steps 1-4 are:

Structure/MS

Example 4 tert-Butyl4-(2-oxo-1,5-diphenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate

The title compound was prepared according to Scheme A, Steps 1-5, andwas obtained as a yellow oil (75%). ESI-MS: m/z 449.4 (M+H)⁺.

Other compounds prepared by Scheme A Steps 1-5 are:

Structure/MS

Example 5 Synthesis of 6-morpholinopyridin-2-amine

A mixture of 2-amino-6-chloropyridine in 100 mL of morpholine was heatedat 225° C. for 60 mins. The mixture was cooled and precipitate filteredoff, the filtrate was concentrated to give the 17 gram product as abrown oil.

Example 6 Synthesis of 6-(3-methoxypropoxy)pyridin-2-amine

Into a 250 mL round bottom flask was added 3-methoxy-propanol (5.26 g,58.4 mmol) and DMF (156 mL). Sodium hydride (60%, 4.67 g, 3 eq) wasadded slowly to the solution. After addition the mixture was heated to90° C. for one hour. 2-chloro-6-amino-pyridine was added and the mixturewas heated to reflux for four hours. LCMS showed conversion to product.The reaction was cooled to room temperature and solvent was removedunder vacuum. The residue was partitioned between water and ethylacetate. Organic layer was separated and the aqueous was extracted threetimes with ethyl acetate (3×50 mL). Organic layer dried over sodiumsulfate and filtered; the solvent was removed under vacuum. The residuewas dissolved with 2N HCl in MeOH and stirred for five hours at roomtemperature; the solvent was removed and the residue was purified bycolumn chromatography with 20% ethyl acetate in hexanes yielding 3.12 g(45%) of the title compound as a yellow oil.

Example 7 Synthesis of 1-(6-(3-Methoxypropoxy)pyridin-2-yl)urea (7B)

Into a 200 mL round bottom flask was added 7A (3.12 g, 17.1 mmol),acetic acid (1.03 g, 1 eq) and water (90 mL). The flask was cooled to 0°C. with an ice bath. Potassium cyanate (2.08 g, 1.5 eq) in water (1.7mL) was slowly syringed into the reaction flask. After addition thereaction was stirred at room temperature overnight. The whiteprecipitate that formed was isolated by filtration on a Buchner funnel.The solid was washed with cold water and dried under vacuum to give theproduct 7B (1.36 g, 35% yield).

Example 8 Synthesis of (3-(bromomethyl)phenyl)(piperidin-1-yl)methanone

Into a 25 mL round bottom flask was added 3-bromomethyl-benzoyl bromide(1.39 g, 5 mmol) and benzene (5 mL). The flask was cooled to 0° C. withan ice bath and piperidine (852 mg, 2 eq) in benzene (3.3 mL) was addedslowly. The reaction was stirred at 0° C. for three hours. Theprecipitate was removed by filtration on a Buchner funnel. The filtratewas concentrated to an oil which was purified by column chromatographywith 20% ethyl acetate in hexanes to give the titled compound as a clearoil (578 mg, 41% yield).

Example 9 Synthesis of 1-(3-methoxypropxy)-3-nitrobenzene

Sodium hydride (95%, 0.4141 g, 17.253 mmol) and anhydrous DMF (50 mL)was stirred at 0° C. under nitrogen for about 10 minutes. A solution of3-nitrophenol (2.0 g, 14.377 mmol) in anhydrous DMF (5 mL) was addeddropwise via addition funnel over 10 minutes. To the mixture, a solutionof 1-bromo-3-methoxypropane (1.613 mL, 15.815 mmol) in anhydrous DMF (5mL) was added dropwise via an addition funnel over 10 minutes. The icebath was removed and the reaction was stirred at RT for about 18 hoursunder nitrogen. The reaction was poured into about 500 mL of ice waterand stirred until mixture reached RT and extracted with ethyl acetate(3×50 mL). The combined organic layers were washed with brine, driedover MgSO₄ and concentrated in vacuo to give the title compound as anamber oil (2.5 g, 83% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.31 (s,3H) 3.66-3.70 (m, 2H) 4.21-4.25 (m, 2H) 7.41-7.45 (m, 1H) 7.57 (t,J=8.34 Hz, 1H) 7.72 (t, J=2.27 Hz, 1H) 7.81 (dd, J=8.08, 1.52 Hz, 1H).ESI-MS: m/z 198.3 (M+H)⁺.

Example 10 Synthesis of 3-(3-methoxypropoxy)aniline (10B)

1-(3-methoxypropoxy)-3-nitrobenzene (10A) (2.0 g, 11.84 mmol) and tinchloride dihydrate (13.36 g, 59.18 mmol) in 25 mL of ethyl acetate wascombined. The mixture was heated at 60° C. for about two hours. Thereaction was then chilled at 0° C. Triethylamine (25-30 mL) was addedslowly until a white precipitate formed. The white precipitate wasfiltered over a Celite plug, washed with brine, and then dried overMgSO₄. The dried filtrate was then concentrated in vacuo and dried undervacuum to provide 10B (2.0 g, 93%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.90(q, J=6.32 Hz, 2H) 3.24 (s, 3 H) 3.44 (t, J=6.32 Hz, 2H) 3.89 (t, J=6.44Hz, 2H) 5.02 (br. s., 2H) 6.05 (dd, J=8.08, 1.26 Hz, 1H) 6.11-6.14 (m,2H) 6.87 (t, J=8.21 Hz, 1H). ESI-MS: m/z 182.3 (M+H)⁺.

Example 11 Synthesis 1-(3-(3-methoxypropoxy)phenyl)urea (11B)

To a flask containing 3-(3-methoxypropoxy)aniline (11A) (2.00 g, 11.04mmol) was charged a 100 mL solution of 80% glacial acetic acid and 20%water. This mixture was chilled to 0° C. A solution of potassium cyanate(1.34 g, 16.56 mmol) in 5 mL of water was slowly added portion-wise tothe reaction mixture. The reaction was then stirred for about 1 hour atRT. The glacial acetic acid was then removed under reduced pressure. Theresulting white solid residue was then rinsed with copious amounts ofwater then dried under vacuum to give title compound 11B (1.70 g, 70%).¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.86-1.95 (m, 2H) 3.24 (s, 3H) 3.46 (t,J=6.32 Hz, 2H) 3.94 (t, J=6.32 Hz, 2H) 5.82 (br. s., 2H) 6.45 (dd,J=8.08, 2.27 Hz, 1H) 6.81 (d, J=7.33 Hz, 1H) 7.00-7.17 (m, 2H) 8.49 (s,1H). ESI-MS: m/z 225.3 (M+H)⁺.

Example 12 Boc-Piperazine Amide Formation

Acid 12A (200 mg, 543 μmol), Boc-piperazine (121 mg, 652 μmol) and EDC(135 mg, 706 μmol) was dissolved with dichloromethane (3.1 mL) andcooled to 0° C. in an ice bath. Diisopropylethylamine (284 μL, 1.63mmol) was added slowly. The ice bath was removed and the reactionmixture was stirred at room temperature overnight. LCMS confirmed theformation of the desired amide and the solvent was removed under vacuum.The residue was purified by column chromatography with 5% MeOH indichloromethane to give 78 mg of the Boc amide 12B (27%).

Example 131-(3-(3-methoxypropoxy)phenyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one(13C)

Amide 13A (79 mg, 147 μmol) was added to a flamed dried round bottomflask under nitrogen and dissolved with 3.9 mL of 1:1 DMF:dioxane. Thesolution was cooled to 0° C. with an ice bath. Sodium hydride (60%, 18mg, 442 μmol) was added at once to the amide solution and stirred at 0°C. for 30 minutes. The ice bath was removed and the reaction mixture wascontinuously stirred at room temperature overnight. LCMS confirmed theformation of the alkylated product. Solvent was removed under vacuum(Step 1).

To the residue, 25% TFA/DCM (3 mL) was slowly added and the solution wasstirred at room temperature for 3 hours. Solvent was removed undervacuum and the residue was redissolved in methanol (2 mL) and purifiedon a PREP LCMS (acetonitrile:water) to obtain 72 mg (45%) of the TFAsalt of 13C.

Example 14 Preparation of1-(3-morpholinophenyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one(14J)

A. Urea synthesis

Aniline 14A (7.29 g, 40.9 mmol) was dissolved with 220 mL of 8:2AcOH:water and cooled to 0° C. with an ice bath. Potassium isocyanate(4.98 g, 61.4 mmol) in 4 mL of water was slowly added to the anilinesolution. After addition, the ice bath was removed and the reactionmixture was stirred at room temperature for one hour. After removingmost of the solvent under vacuum, the residue was made basic by additionof saturated sodium bicarbonate. The precipitate formed was isolated byfiltration on Buchner funnel, and was washed with diethyl ether. A tansolid 14B was obtained (6.25 g, 69%) which was used in the next stepwithout further purification.

B. Urea Insertion to Diazocarbonyl

Urea 14B (2.65 g, 12 mmol) was ground into a fine powder with a mortarand pestle and suspended in 90 mL of 1:1 dichloroethane:toluene in a 250mL flask. Diazocarbonyl 14C (1.74 g, 8 mmol) was added and the mixturewas degassed by bubbling nitrogen through the solution for 15 minutes.After degassing, the flask was fitted with a reflux condenser connectedto nitrogen source, the flask was heated to 80° C. Rhodium catalyst (125mg, 0.16 mmol) was suspended in 18 mL of toluene and sonicated to make afine suspension. The suspension was taken up in a syringe and addedslowly to the urea 14B and diazocarbonyl 14C solution over 15 minutes.After addition, the flask was heated for one hour. The flask was cooledand the solvent was removed under vacuum to leave an oily residue 14Dwhich was used in the next step without further purification.

C. Urea Cyclization

The residue 14D obtained from the previous step was dissolved withtrifluoroacetic acid (50 mL) and acetic anhydride (25 mL). The mixturewas heated to 85° C. for 4 hours. Solvent was removed under vacuum toleave a residue 14E which was used in the next step without furtherpurification.

D. Ester Hydrolysis

The residue 14E from the previous step was dissolved with 1,4-dioxane(30 mL) and ethanol (15 mL). Sodium hydroxide (3 g) in water (5 mL) wasadded to the solution and the mixture was heated at 80° C. for 2 hours.The reaction was cooled and solvent was removed under vacuum. Theresidue was redissolved with water (15 mL) and acidified with 6N HCl topH=5.

The aqueous layer was extracted with ethyl acetate (2×30 mL). Theaqueous was acidified to pH=3 and extracted with ethyl acetate (2×30mL). The aqueous layer was acidified to pH=1 and extracted with ethylacetate (2×30 mL). The organic layers are combined and washed with brine(1×) and dried over sodium sulfate. The solvent was removed under vacuumto leave a brown oil (3.38 g). The residue was purified by columnchromatography with 5% MeOH/DCM to give 1.15 g (39%) of a brown solid14F.

E. Boc-Piperazine Amide Formation

Acid 14F (150 mg, 411 μmol), Boc-piperazine 14G (92 mg, 493 μmol) andEDC (102 mg, 534 μmol) was dissolved with dichloromethane (2.3 mL). Themixture was cooled to 0° C. with an ice bath. Diisopropylethylamine (215μL, 1.23 mmol) was added slowly. The ice bath was removed, and thereaction mixture was stirred overnight at room temperature. Solvent wasremoved under vacuum and the residue was purified on a preparative LCMS(water:acetonitrile) to give the amide 14H (104 mg, 47%).

F. Alkylation and Deprotection

Amide 14H (53 mg, 99 μmol) was added to a flamed dried round bottomflask under nitrogen. The amide was dissolved with 2.6 mL of 1:1DMF:dioxane. The solution was cooled to 0° C. with an ice bath. Sodiumhydride (60%, 12 mg, 298 μmol) was added at once to the amide solutionand stirred at 0° C. for 30 minutes. The ice bath was removed andstirred at room temperature overnight. LCMS confirmed the formation ofthe alkylated product. Solvent was removed under vacuum. To the residue,25% TFA/DCM (3 mL) was slowly added, and the solution was stirred atroom temperature for 3 hours. Solvent was removed under vacuum and theresidue was redissolved in methanol (2 mL) and purified on a preparativeLCMS (acetonitrile:water) to obtain 72 mg (67%) of the TFA salt of 14J.

Example 15

A. Synthesis of1-((1R,2R)-2-(benzyloxy)cyclohexyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylicacid (15E) A.1: Synthesis of 1-((1R,2R)-2-(benzyloxy)cyclohexyl)urea(15B)

Combined (1R,2R)-2-(benzyloxy)cyclohexanamine 15A (4.0 g, 19.48 mmol)and KCNO (1.58 g, 19.48 mmol) in 24 mL of water. The mixture was chilledto 0° C. and then glacial acetic acid (1.17 mL, 19.48 mmol) was added.The ice bath was removed and a precipitate was observed after 2 hours.The reaction was stirred overnight at RT. The white solid was filtered,rinsed with water and dried under vacuum to provide 15B (3.20 g, 66%).¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15-1.27 (m, 2H) 1.50 (d, J=3.03 Hz,1H) 1.61 (dd, J=5.68, 2.91 Hz, 1H) 1.81 (dd, J=8.59, 2.78 Hz, 1H) 1.91(dd, J=14.27, 4.17 Hz, 1H) 3.18 (td, J=8.27, 3.92 Hz, 1H) 3.32 (s, 2H)3.42-3.51 (m, 1H) 4.45-4.56 (m, 1H) 4.50 (d, J=19.71 Hz, 1H) 5.37 (s,2H) 5.93 (d, J=8.08 Hz, 1H) 7.25 (td, J=5.31, 2.78 Hz, 1H) 7.32 (d,J=4.80 Hz, 4H). ESI-MS: m/z 249.4 (M+H)⁺.

A.2: Synthesis of1-((1R,2R)-2-(benzyloxy)cyclohexyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylicacid (15E)

A flask containing a mixture of 15B (3.20 g, 12.87 mmol), ethyl2-diazo-3-oxo-3-phenylpropanoate (15C) (2.25 g, 10.31 mmol), and 103 mLof 1:1 toluene:dichloroethane was heated at 80° C. for about 10 minutes.A suspension of rhodium octanoate dimer (0.16 g, 0.21 mmol) in 25 mLtoluene was added dropwise to the reaction mixture via addition funnel.The reaction was held at 80° C. for an additional hour after additionwas completed. After the disappearance of 15C, the reaction was cooledto RT. Approximately 8 mL of TFA was then added and the reaction wasallowed to stir overnight at RT. The reaction mixture was concentratedto a green oil then purified by flash chromatography on silica gel using5-40% ethyl acetate/hexanes to afford the desired product ethyl1-((1R,2R)-2-(benzyloxy)cyclohexyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylateas a tan solid (15D) (2.20 g, 49%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.96(t, J=7.07 Hz, 4H) 1.16 (d, J=12.13 Hz, 1H) 1.56-1.67 (m, 2H) 1.72 (d,J=12.13 Hz, 1H) 2.11 (d, J=6.82 Hz, 1H) 2.32 (d, J=8.84 Hz, 1H) 3.25(br. s., 1H) 3.98 (q, J=7.07 Hz, 2H) 4.19-4.31 (m, 3H) 4.51 (d, J=11.87Hz, 1H) 7.15 (d, J=7.33 Hz, 2H) 7.23-7.34 (m, 1H) 7.28 (dd, J=7.71, 1.64Hz, 4H) 7.43 (br. s., 3H) 10.86 (s, 1H). ESI-MS: m/z 421.4 (M+H)⁺.

Combined 15D (1.0 g, 2.38 mmol), 9 mL of ethyl alcohol and 9 mL of 1NNaOH. The mixture was heated at 90° C. overnight. After thedisappearance of the starting materials by LC/MS, the reaction wascooled to RT and approximately 20 mL of 1N HCl was added directly. Theaqueous mixture was extracted with ethyl acetate (3×20 mL), washed withbrine, dried over MgSO₄ and concentrated in vacuo to afford1-((1R,2R)-2-(benzyloxy)cyclohexyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylicacid (15E) as an oil (0.8 g, 86%). This oil was used in next stepwithout purification. ESI-MS: m/z 393.2 (M+H)⁺.

B. Synthesis of tert-butyl4-((1R,2R)-2-(benzyloxy)cyclohexyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1-imidazole-4-carbonyl)piperazine-1-carboxylate(15G^(a))

Dissolved 15E (1.5 g, 3.82 mmol) in 15 mL of DMF and added EDC (1.28 g,6.68 mmol) and HOBt (0.88 g, 6.49 mmol). The mixture was stirred for atleast 15 minutes. Next, DIEA (2.0 mL, 11.4 mmol) was added along withtert-butyl piperazine-1-carboxylate (0.85 g, 4.58 mmol). This reactionmixture was then stirred overnight at RT. After the disappearance of15E, this mixture was poured into 150 mL of water. The white solid wasfiltered, rinsed with water and dried under vacuum to provide tert-butyl4-(1-((1R,2R)-2-(benzyloxy)cyclohexyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate(15G^(a)) (1.6 g, 75%). ESI-MS: m/z 561.6 (M+H)⁺.

C. Synthesis of tert-butyl4-(3-benzyl-1-((1R,2R)-2-(benzyloxy)cyclohexyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1-imidazole-4-carbonyl)piperazine-1-carboxylate(15H)

Sodium hydride (0.02 g, 0.86 mmol) was added to a 50 mL flask underblanket of nitrogen; to this, 4 mL of anhydrous DMF was added. Whilestirring, 15G^(a) (0.4 g, 0.71 mmol) was added along with the remaining4 mL of anhydrous DMF. After the reaction mixture was chilled at 0° C.for 15 mins, a solution benzyl bromide (0.10 mL, 0.86 mmol) in 1 mL wasadded slowly. The mixture was stirred in the ice bath for about twohours. At this time point, LC/MS and TLC showed at least 30% of thestarting material remained. The reaction was stirred overnight undernitrogen. The next day, LC/MS shows about 10% of the starting materialremained. Reaction was quenched by pouring into 50 mL of ice water. Thisaqueous mixture was extracted with ethyl acetate, washed with brine anddried over MgSO₄ to give crude product. The crude product was purifiedby flash chromatography using 5% MeOH in DCM to afford 15H as an oil(0.21 g, 45%). ESI-MS: m/z 651.4 (M+H)⁺.

D. Synthesis of tert-butyl4-(3-benzyl-1-((1R,2R)-2-hydroxycyclohexyl)-2-oxo-5-phenyl-2,3-dihydro-1H-1-imidazole-4-carbonyl)piperazine-1-carboxylate(15J)

10 mL of methanol was added to a flask containing 15H (0.21 g, 0.32mmol) and 10% Pd/C (0.02 g). The reaction flask was evacuated and purgedwith hydrogen then stirred under a balloon of hydrogen at RT. Afterabout two hours, the reaction had fully converted to desired product asconfirmed by LC/MS and TLC. The mixture was filtered over a pad ofCelite and filtrate was concentrated in vacuo. The residue wasreconstituted in ethyl acetate, washed with brine, dried over MgSO₄ andconcentrated to give 15J, as a glassy oil in quantitative yield. ESI-MS:m/z 561.4 (M+H)⁺.

E. Synthesis of (R)-tert-butyl 3-(benzamidomethyl)piperazine-1-carboxylate (15F^(b)) E1: (S)-tert-butyl3-(hydroxymethyl)piperazine-1-carboxylate (15L)

Into a 200 mL round bottom flask was added(S)-(4-benzylpiperazin-2-yl)methanol (15K) (10.3 g, 50 mmol) andmethanol (100 mL). Palladium hydroxide on carbon (3.0 g) was added andthe flask was cycled with hydrogen and vacuum five times. The flask wasstirred at room temperature with atmospheric hydrogen overnight. Thereaction was filtered through Celite with a Buchner funnel. The filtratewas cooled to −15° C. Boc anhydride (10.9 g, 1 eq) was slowly added tothe methanol solution. Upon complete addition the flask was warmed to 0°C. and stirred for two hours. The flask was warmed to room temperatureand solvent was removed under vacuum. The residue was purified by columnchromatography using 4:2 ethyl acetate:methanol to give 15L as an oil(11.01 g, 85%).

E2: (S)-tert-butyl 4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate(15N)

Into a 250 mL round bottom flask was added 15L (10.93 g, 50.5 mmol) and1,2-dichloroethane (144 mL). Acetic acid (3.03 g, 1 eq) was added andthe flask was cooled to 0° C. Sodium triacetoxyborohydride (13.91 g, 1.3eq) was slowly added. The flask was warmed to room temperature andstirred overnight at room temperature. The reaction mixture was pouredonto saturated sodium bicarbonate. The organic layer was separated andthe aqueous was extracted two times with ethyl acetate. The organic werecombined and washed once with brine. The organics were dried over sodiumsulfate and filtered. Solvent was removed under vacuum. The residue waspurified by column chromatography with 50% ethyl acetate in hexanes togive a white solid 15N (13.07 g, 84%).

E3: (R)-tert-butyl4-benzyl-3-((1,3-dioxoisoindolin-2-yl)methyl)piperazine-1-carboxylate(15R)

Into a 100 mL round bottom flask was added 15P (3.5 g, 11.4 mmol) andTHF (52 mL). DEAD (2.98 g, 1.5 eq), triphenylphosphine (4.49 g, 1.5 eq)and phthalimide 15Q (2.52 g, 10.5 eq) were added in succession. Thereaction was stirred overnight at room temperature. The solvent wasremoved under vacuum and the residue was purified by columnchromatography with 5% methanol in dichloromethane to give 15R as awhite solid (5.87 g, 92%).

E4: (R)-tert-butyl 3-(aminomethyl)-4-benzylpiperazine-1-carboxylate(15S)

Into a 200 mL round bottom flask was added 15R (6.66 g, 15.3 mmol) and110 mL of 10:1 dichloromethane:ethanol. Hydrazine hydrate (7.66 g, 10equiv.) was added and the reaction was heated to reflux for three hours.The precipitate which had formed was removed by filtration throughCelite. The filtrate was concentrated under high vacuum and temperature(to remove hydrazine). The residue was resuspended in dichloromethaneand the resultant precipitate was removed by filtration through aBuchner funnel. The filtrate was concentrated to leave a clear oil 15S(3.27 g, 73%) which was analytically pure.

E5: (R)-tert-butyl 3-(benzamidomethyl)-4-benzylpiperazine-1-carboxylate(15U)

Into a 50 mL round bottom flask was added 15S (820 mg, 2.68 mmol) anddichloromethane (15 mL). Benzoic acid (15T) (426 mg, 1.3 eq) and EDC(669 mg, 1.3 eq) was added and the flask was cooled to 0° C. DIEA (1.04g, 3 equiv.) was slowly added and the reaction was stirred at roomtemperature overnight. The solvent was removed under vacuum and theresidue was purified by column chromatography with 5% methanol indichloromethane to give 15U as a solid (865 mg, 79%).

E6: (R)-tert-butyl 3-(benzamidomethyl)piperazine-1-carboxylate (15F^(b))

Into a 40 mL scintillation vial was added 15U (865 mg, 2.11 mmol) andmethanol (21 mL). The solution was passed through the H-Cubehydrogentator three times at 40 psi of hydrogen pressure at 50° C. Theresultant solution was concentrated under vacuum and the residue waspurified by column chromatography with 5% methanol in dichloromethane togive (R)-tert-butyl 3-(benzamidomethyl)piperazine-1-carboxylate(15F^(b)) as an oil (550 mg, 81%).

F. Synthesis of tert-butyl4-(3-benzyl-1-((1R,2R)-2-hydroxycyclohexyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate(15G^(b))

Dissolved 15E (0.20 g, 0.48 mmol) in 2.5 mL of DMF and added EDC (0.16g, 0.83 mmol) and HOBt (0.11 g, 0.81 mmol). The mixture was stirred forat least 15 minutes. Next, DIEA (0.25 mL, 1.47 mmol) was added alongwith 15F^(b) (0.16 g, 0.50 mmol). This reaction mixture was then stirredat RT for about two hours. After the disappearance of 15E, this mixturewas poured into 40 mL of water. The white solid was filtered, rinsedwith water and dried under vacuum to provide 15G^(b) (0.21 g, 64%).ESI-MS: m/z 693.5 (M+H)⁺.

Example 16 Synthesis of tert-butyl4-(1-(1-acetylpiperidin-3-yl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate(16F)

A. Synthesis of benzyl 3-ureidopiperidine-1-carboxylate (16B)

Benzyl 3-aminopiperidine-1-carboxylate (16A) (5.0 g, 21.34 mmol) wascombined with KCNO (1.73 g, 21.34 mmol) in water (24 mL). The mixturewas chilled to 0° C. and then glacial acetic acid (1.28 mL, 21.34 mmol)was added. The ice bath was removed and a precipitate was observed after2 hours. The reaction mixture was stirred overnight at RT. The whitesolid was filtered, rinsed with water and dried under vacuum to providebenzyl 3-ureidopiperidine-1-carboxylate (16B) (2.90 g, 49%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.20-1.44 (m, 2H) 1.53-1.69 (m, 1H) 1.75 (dd,J=11.87, 3.28 Hz, 1H) 2.63-3.14 (m, 2H) 3.40-3.83 (m, 3H) 5.06 (d,J=3.03 Hz, 2H) 5.43 (s, 2H) 6.02 (br. s., 1H) 7.25-7.41 (m, 5H) ESI-MS:m/z 278.2 (M+H)⁺.

B. Synthesis of benzyl3-(4-(ethoxycarbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate(16D)

A flask containing a mixture of ethyl 2-diazo-3-oxo-3-phenylpropanoate(16C) (2.80 g, 12.84 mmol), 16B (4.45 g, 16.05 mmol) from previous step,and 128 mL of 1:1 toluene:dichloroethane was heated at 80° C. for about10 minutes. A suspension of rhodium octanoate dimer (0.20 g, 0.26 mmol)in 25 mL toluene was added dropwise to the reaction mixture via anaddition funnel. The reaction was held at 80° C. for an additional hourafter the addition was completed. After the disappearance of 16C, thereaction was cooled to RT. Approximately 8 mL of TFA was then added andthe reaction was allowed to stir overnight at RT. The reaction mixturewas concentrated to a green oil then purified by flash chromatography onsilica gel using 5% methanol/DCM to afford benzyl3-(4-(ethoxycarbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate(16D) as a tan solid (2.50 g, 42%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.94(t, J=7.07 Hz, 3H) 1.07-1.18 (m, 2H) 1.24 (br. s., 1H) 1.62-1.78 (m, 2H)2.36-2.43 (m, 1H) 2.59-2.68 (m, 1H) 3.46-3.58 (m, 2H) 3.96 (q, J=6.91Hz, 2H) 4.99 (s, 1H) 7.26-7.51 (m, 11H) 10.97 (s, 1H) ESI-MS: m/z 450.1(M+H)⁺.

C. Synthesis of1-(1-(benzyloxycarbonyl)piperidin-3-yl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylicacid, (16E)

(16D) (2.6 g, 5.78 mmol) prepared in the previous step was combined with26 mL of dioxane and 29 mL of 1N LiOH. The mixture was heated at 55° C.overnight. After the disappearance of 16D as monitored by LC/MS, thereaction was cooled to RT and approximately 50 mL of 1N HCl was addeddirectly. The aqueous mixture was extracted with ethyl acetate (3×40mL), washed with brine, dried over MgSO₄, and concentrated in vacuo toafford1-(1-(benzyloxycarbonyl)piperidin-3-yl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carboxylicacid as an oil (16E) (2.43 g, quantitative yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.13 (d, J=9.60 Hz, 1H) 1.25 (br. s., 1H) 1.61-1.77 (m,2H) 2.60 (br. s., 1H) 3.25 (br. s., 1H) 3.84-4.00 (m, 2H) 4.99 (s, 2H)7.27-7.47 (m, 10H) 7.92-7.97 (m, 1H) 10.79 (s, 1H) 12.43 (br. s., 1H).This was used in next step without purification. ESI-MS: m/z 422.3(M+H)⁺.

D. Synthesis of tert-butyl4-(1-(1-(benzyloxycarbonyl)piperidin-3-yl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate(16F)

Dissolved 16E (3.0 g, 7.118 mmol) prepared in the previous step in 30 mLof DMF and added EDC (2.39 g, 12.46 mmol) and HOBt (1.65 g, 12.01 mmol).The mixture was stirred for at least 15 minutes. Next, DIEA (2.76 mL,21.35 mmol) was added along with tert-butyl piperazine-1-carboxylate(1.39 g, 7.47 mmol). This reaction mixture was then stirred at RT forabout four hours. After the disappearance of 16E, this mixture waspoured into 300 mL of water, a white precipitate was formed. The whitesolid was filtered, rinsed with water and dried under vacuum to providetert-butyl4-(1-(1-(benzyloxycarbonyl)piperidin-3-yl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate(16F) (3.2 g, 76%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (s, 9H) 1.40(s, 2H) 1.65-1.80 (m, 4H) 2.34 (br. s., 1H) 2.83 (br. s., 4H) 3.13-3.19(m, 4H) 3.94-4.07 (m, 2H) 5.03 (s, 2H) 7.23-7.50 (m, 10H) 10.73 (s, 1H).ESI-MS: m/z 590.1 (M+H)⁺.

E. Synthesis of tert-butyl4-(2-oxo-5-phenyl-1-(piperidin-3-yl)-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate(16G)

10 mL of methanol was added to a flask containing 16F (0.50 g, 0.85mmol) prepared in the previous step and 10% Pd/C (0.05 g). The reactionflask was evacuated and purged with hydrogen, then stirred under aballoon of hydrogen overnight at RT. The mixture was filtered over a padof Celite and the filtrate was concentrated in vacuo. The residue wasreconstituted in ethyl acetate, washed with brine, dried over MgSO₄, andconcentrated to give tert-butyl4-(2-oxo-5-phenyl-1-(piperidin-3-yl)-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate(16H), as a glassy oil in quantitative yield. ESI-MS: m/z 456.4 (M+H)⁺.

F. Synthesis of tert-butyl4-(1-(1-acetylpiperidin-3-yl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate(16H)

16G (0.39 g, 0.85 mmol) prepared in the previous step was dissolved in 3mL of anhydrous DCM. TEA (0.36 mL, 2.54 mmol) was added and the mixturewas chilled to 0° C. To this chilled mixture, acetic anhydride (0.08 mL,0.85 mmol) was added slowly. After about 30 minutes, TLC and LC/MSshowed no signs of 16G. At this point, the mixture was concentrated togive tert-butyl4-(1-(1-acetylpiperidin-3-yl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate(16H) as an oil (0.42 g, quantitative yield). ESI-MS: m/z 498.4 (M+H)⁺.

Example 17

2,6-dichloro-4-(chloromethyl)pyridine was alkylated to 17A according togeneral procedure, Scheme A, Step 7, to afford tert-butyl4-(1-cyclohexyl-3-((2,6-dichloropyridin-4-yl)methyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate17B.

17B was treated with 1.5 eq of (R)-pyrrolidin-3-ol and 5 equiv. ofNa₂CO₃ in isopropanol under micro-wave condition at 180° C. for 30 min.The crude mixture was then treated with TAF-DCM (1:1) for 2 hr, purifiedby LCMS to give both 17C and 17D and their associated stereoisomers.

17C¹:(S)-1-((2-Chloro-6-(3-hydroxypyrrolidin-1-yl)pyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one.¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.42 (m, H), 7.15 (m, 2H), 6.26 (s,1H), 6.04 (s, 1H), 4.81 (br. s., 2H), 4.44 (br. s., 2H), 3.41 (m, 4H),3.32 (s, 1H), 2.26 (m, 4H), 2.00 (m, 2H), 1.75-1.65 (m, 4H), 1.53 (d,J=11.87 Hz, 1H), 1.12 (m, 4H). ESI-MS: calc'd for C₃₀H₃₈ClN₆O₃, 565.3.found 565.3 (M+H)⁺.

17C²:(R)-1-((2-Chloro-6-(3-hydroxypyrrolidin-1-yl)pyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one.¹H-NMR (400 MHz, CDCl₃-CD₃OD 10:1) δ ppm 7.42 (m, 3H), 7.15 (m, 2H),6.26 (s, 1H), 6.04 (s, 1H), 4.44 (br. s., 2H), 3.52 (ddd, J=12.1, 8.4,3.5 Hz, 2H), 3.40 (m., 4H), 2.28 (m., 5H), 1.95-2.15 (m, 2H), 1.75-1.65(m., 4H), 1.51 (d., J=8.0 Hz, 1H), 1.10-125 (m, 4H). ESI-MS: calc'd forC₃₀H₃₈ClN₆O₃, 565.3. found 565.3 (M+H)⁺.

17D¹:1-((2,6-bis((S)-3-Hydroxypyrrolidin-1-yl)pyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one.¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.44 (m, 3H), 7.17 (m, 2H), 4.76(br. s., 2H), 4.47 (br. s., 2H), 3.17 (br. s., 2H), 2.27 (m., 2H), 2.04(br. s., 4H), 1.75 (m, 2H), 1.65 (m, 2H), 1.53 (m, 2H), 1.03-1.25 (m,4H). ESI-MS: calc'd for C₃₄H₄₆N₇O₄, 616.4. found 616.4, (M+H)⁺.

17D²:1-((2,6-bis((R)-3-Hydroxypyrrolidin-1-yl)pyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one.¹H-NMR (400 MHz, CDCl₃-CD₃OD 10:1) δ ppm 7.42 (m, 3H), 7.16 (m, 2H),6.4, 6.2 (1H each), 4.5 (s, 2H), 2.26 (m, 2H), 2.03 (m, 4H), 1.75 (m,2H), 1.66 (m, 1H), 1.05-123 (m., 4H). ESI-MS: calc'd for C₃₄H₄₆N₇O₄,616.4. found 616.4, (M+H)⁺.

A mixture of 1.0 eq of compound 17B, 1.2 eq of6-methoxypyridin-3-ylboronic acid, 5 eq of Na₂CO₃ and tetrakis(triphenyl phosphine) palladium (0.01 equiv.) in dioxane-H₂O (20:1) wastreated under micro-wave condition at 160° C. for 20 min, purified byLCMS to give 17E, 17F, and 17G.

17E:1-Cyclohexyl-3-((2,6-di(2-methoxyl-pyridine-4-yl)pyridin-4-yl)methyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one.¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.68 (d, J=2.0 Hz, 2H), 8.25 (dd,J=8.8, 2.5 Hz, 2H), 7.43 (s, 2H), 7.37 (m, 3H), 7.14 (m, 2H), 6.77 (d,J=8.8 Hz, 2H), 5.17 (s, 1H), 4.92 (s, 2H), 3.85 (s, 6H), 3.33-3.56 (m,1H), 3.09 (m, 4H), 2.06-2.30 (m, 4H), 1.68 1.59 (m, 4H), 1.45 (m, 1H),0.94-1.17 (m, 4H). ESI-MS: calc'd for C₃₈H₄₂N₇O₄, 660.3. found 660.3,(M+H)⁺.

17F:1-Cyclohexyl-3-((6′-methoxy-2,3′-bipyridin-4-yl)methyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one.¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.52 (dd, J=2.5, 0.8 Hz, 1H), 8.43(dd, J=5.3, 0.5 Hz, 1H), 8.04 (dd, J=2.6, 8.9 Hz, 1H), 7.55 (s, 1H),7.39 (m, 3H), 7.13 (m, 2H), 7.06 (dd, J=5.2, 1.6 Hz, 1H), 6.75 (dd,J=9.9, 1.8 Hz, 1H), 4.90 (s, 2H), 3.83 (m, 3H), 3.22 (s, 3H), 2.24 (m,4H), 1.57-1.69 (m, 4H), 1.45 (m, 1H), 1.03 (m, 4H). ESI (MS) calc'd forC₃₂H₃₇N₆O₃, 553.3. found 553.3, (M+H)⁺.

17G:1-((6-chloro-6′-methoxy-2,3′-bipyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one.MS (ES) [m+H] calc'd for C₃₂H₃₆N₆O₃Cl, 587.3. found 587.3.

17G (0.2 mmol) was treated with (1 mmol, 1.5 eq) of either dimethyamineor diethylamine and 5 equiv. of Na₂CO₃ in 2 mL of isopropanol undermicro-wave condition at 180° C. for 30 min. The crude mixture was thentreated with TFA-DCM (1:1) for 2 h, purified by LCMS to give either thedimethyl substituted 17H or the diethyl substituted 17J.

17H:1-cyclohexyl-3-((6-(dimethylamino)-6′-methoxy-2,3′-bipyridin-4-yl)methyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one.¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.55 (d, J=2.6 Hz, 1H), 8.07 (dd,J=2.6, 8.6 Hz, 1H), 7.34 (m, 1H), 7.26 (m, 1H), 7.09 (m, 1H), 6.65 (m,1H), 6.18 (s, 1H), 4.78 (s, 2H), 3.80 (s, 3H), 2.96 (s, 6H), 2.23 (m,4H), 1.56-1.71 (m, 4H), 1.45 (m, 1H), 1.03 (m, 4H). ESI-MS: calc'd forC₃₄H₄₂N₇O₃, 596.3. found 596.3, (M+H)⁺.

17J:1-cyclohexyl-3-((6-(diethylamino)-6′-methoxy-2,3′-bipyridin-4-yl)methyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one.¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.44 (d, J=2.5 Hz, 1H), 7.98 (dd,J=2.5, 8.8 Hz, 1H), 7.37 (m, 3H), 7.11 (m, 2H), 6.71 (d, J=8.5 Hz, 1H),6.64 (s, 1H), 6.39 (s, 1H), 4.77 (br. s., 2H), 3.83 (s, 3H), 3.45 (q,J=7 Hz, 4H), 3.11 (m, 3H), 2.20 (m., 1H), 1.68 (m, 2H), 1.60 (m, 2H),1.45 (m, 1H), 1.08 (t, J=7.07 Hz, 6H), 1.03 (m, 4H). ESI-MS: calc'd forC₃₆H₄₆N₇O₃, 624.4. found 624.4, (M+H)⁺.

Example 18 1,5-Diphenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 2.7 (br s, 4H) 3.6 (br s, 4H)7.17 (m, 4H) 7.36 (m, 6H). ESI-MS: m/z 349.4 (M+H)⁺.

Example 195-Phenyl-4-(piperazine-1-carbonyl)-1-(pyridin-2-yl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.73 (br s, 4H), 3.48 (brs, 4H), 7.03 (m, 2H), 7.26-7.36 (m, 4H), 7.55 (d, 1H), 7.94 (t, 1H),8.30 (d, 1H), 8.77 (br s, 1H), 11.07 (s, 1H). ESI-MS: m/z 350.4 (M+H)⁺.

Example 204-(2-(Hydroxymethyl)piperazine-1-carbonyl)-1,5-diphenyl-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 2.7-3.3 (m, 9H) 7.17-7.43 (m,10H). ESI-MS: m/z 379.4 (M+H)⁺.

Example 215-(3-Fluorophenyl)-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 2.8 (br s, 4H) 3.6 (br s, 4H)6.95 (m, 2H) 7.3-7.45 (m, 7H); ESI-MS: m/z 367.4 (M+H)⁺.

Example 221-(3-Morpholinophenyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ESI-MS: m/z 434.4 (M+H)⁺.

Example 235-Isopropyl-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 1.12 (d, J=7.07 Hz, 6H)2.63-2.85 (m, 1H) 3.23-3.27 (m, 2H) 3.34-3.38 (m, 2H) 3.77-3.99 (m, 3H)7.35 (dd, J=8.08, 1.52 Hz, 2H) 7.45-7.64 (m, 3H). ESI-MS: m/z 315.4(M+H)⁺.

Example 245-Cyclopropyl-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 0.28-0.51 (m, 2H) 0.60-0.85(m, 2H) 1.51-1.79 (m, 1H) 3.75-4.15 (m, 8H) 7.39-7.49 (m, 3H) 7.49-7.59(m, 2H). ESI-MS: m/z 313.2 (M+H)⁺.

Example 255-(Cyclopropylmethyl)-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 0.10-0.44 (m, 4H) 0.49-0.72(m, 1H) 2.45 (d, J=6.82 Hz, 2H) 3.71-4.08 (m, 8H) 7.23-7.46 (m, 2H)7.44-7.76 (m, 3H). ESI-MS: m/z 327.2 (M+H)⁺.

Example 265-(2-Chlorophenyl)-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 2.65-2.96 (m, 4H) 3.45-3.74(m, 4H) 7.08-7.18 (m, 2H) 7.24-7.52 (m, 7H). ESI-MS: m/z 383.2 (M+H)⁺.

Example 271-(3-(2-methoxyethoxy)benzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one

A. (3-(2-methoxyethoxy)phenyl)methanol, 27C

To a solution of 3-hydroxybenzyl alcohol (27A) (12.41 g, 100 mmol) inethanol (150 mL) was added aqueous NaOH (10 N, 10 mL), followed by1-bromo-2-methoxyethane (27B) (13.9 g). The reaction mixture was heatedto reflux overnight. Then the reaction mixture was allowed to cool toRT, and diluted with water. The mixture was subsequently extracted withCH₂Cl₂, and the combined organic phase was dried with anhydrous MgSO₄filtered, and concentrated in vacuum to give the product (27C) a yellowoil, which was used for the next reaction without further purification.¹H NMR (300 MHz, CDCl₃): δ 1.82 (br, 1H), 3.44 (s, 3H), 3.74 (t, 2H,J=4.8 Hz), 4.12 (t, 2H, J=4.8 Hz), 4.65 (s, 2H), 6.84-6.95 (m, 3H),7.22-7.26 (m, 1H). LCMS: purity >94%. ESI-MS: M/Z 183(M+H)⁺.

B. 1-(bromomethyl)-3-(2-methoxyethoxy)benzene, 27D

To a solution of 27C (18.2 g, 100 mmol) in CH₂Cl₂ (300 mL) was addedPBr₃ (4.5 mL, 48 mmol) at 0° C., then the resulting mixture was allowedto warm to RT overnight. The reaction mixture was quenched withsaturated NaHCO₃ (50 mL) and stirred at RT for an addition 0.5 h. Themixture was extracted with CH₂Cl₂, and the combined extracted were dried(MgSO₄), filtered, and evaporated in vacuum to give the product as ayellow oil (20.2 g, 82%, two steps). ¹H NMR (300 MHz, CDCl₃): δ 3.45 (s,1H), 3.75 (t, 2H, J=4.8 Hz), 4.12 (t, 2H, J=4.8 Hz), 4.45 (s, 2H),6.85-6.99 (m, 3H), 7.21-7.26 (m, 1H). LC-MS: purity >95%, ESI-MS: M/Z245 (M+H)⁺, 247 (M+2+H)⁺.

C.1-(3-(2-methoxyethoxy)benzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one

The title compound 27F was prepared according to general procedure,Scheme A, Steps 7 and 8. ESI-MS: m/z 527.2 (M+H)⁺.

Example 285-(4-Chlorophenyl)-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 2.74-3.01 (m, 4H) 3.49-3.70(m, 4H) 7.06-7.25 (m, 5H) 7.28-7.45 (m, 2H). ESI-MS: m/z 383.2 (M+H)⁺.

Example 291-Cyclohexyl-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 0.96-1.31 (m, 4H) 1.59-1.88(m, 4H) 2.18-2.44 (m, 2H) 3.16-3.29 (m, 4H) 3.40-3.68 (m, 4H) 7.26-7.49(m, 2H) 7.48-7.70 (m, 3H). ESI-MS: m/z 355.3 (M+H)⁺.

Example 30 Benzyl3-(2-oxo-5-phenyl-4-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ESI-MS: m/z 490.1 (M+H)⁺.

Example 311-((1R,2R)-2-(Benzyloxy)cyclohexyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ESI-MS: m/z 461.3 (M+H)⁺.

Example 321-(2-(2-Methoxyethoxy)phenyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one5.3/5.4

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 3.34 (s, 3H) 3.49-3.70 (m,8H) 3.81-3.94 (m, 2H) 4.00-4.09 (m, 2H) 6.92-7.08 (m, 4H) 7.20 (dd,J=7.96, 1.64 Hz, 2H) 7.24-7.40 (m, 5H). ESI-MS: m/z 423.2 (M+H)⁺.

Example 331-(2-(3-Methoxypropoxy)phenyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 1.76-1.93 (m, 2H) 2.64 (br.s., 2H) 2.76 (br. s., 2H) 3.31 (s, 3H) 3.42 (t, J=6.19 Hz, 2H) 3.49-3.71(m, 4H) 3.76-4.03 (m, 4H) 6.91-7.06 (m, 2H) 7.17 (dd, J=7.96, 1.64 Hz,2H) 7.26-7.42 (m, 5H). ESI-MS: m/z 437.3 (M+H)⁺.

Example 341-(3-(2-Methoxyethoxy)phenyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H (400 MHz, DMSO-d₆) δ ppm 1.24 (s, 1H), 2.27 (d, J=9.60Hz, 4H), 3.16 (s, 4H), 3.26 (s, 3H), 3.56 (dd, J=3.79, 2.27 Hz, 2H),3.96 (dd, J=5.31, 3.79 Hz, 2H), 6.66 (dd, J=8.08, 1.01 Hz, 1H), 6.73 (t,J=2.15 Hz, 1H), 6.85 (dd, J=8.08, 2.27 Hz, 1H), 7.04 (dd, J=7.20, 2.40Hz, 2H), 7.21 (t, J=8.08 Hz, 1H), 7.26-7.32 (m, 3H), 10.91 (s, 1H).ESI-MS: m/z 423.4 (M+H)⁺.

Example 351-(3-(3-Methoxypropoxy)phenyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H (400 MHz, DMSO-d₆) δ ppm 0.85 (d, J=6.82 Hz, 1H), 1.24(s, 2H), 1.78-1.88 (m, J=6.32, 6.32, 6.32, 6.32 Hz, 2H), 2.28 (ddd,J=14.27, 4.17, 4.04 Hz, 3H), 3.18 (dd, J=8.59, 4.80 Hz, 3H), 3.23 (s,3H), 3.40 (t, J=6.19 Hz, 2H), 3.90 (t, J=6.44 Hz, 2H), 6.64 (dd, J=7.96,0.63 Hz, 1H), 6.73 (t, J=2.02 Hz, 1H), 6.83 (dd, J=8.21, 2.15 Hz, 1H),7.04 (d, J=9.60 Hz, 1H), 7.04 (d, J=3.28 Hz, 1H), 7.20 (t, J=8.08 Hz,1H), 7.24-7.32 (m, 1H), 7.28 (d, J=1.77 Hz, 2H), 10.91 (s, 1H). ESI-MS:m/z 437.4 (M+H)⁺.

Example 361-(6-(3-Methoxypropoxy)pyridin-2-yl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 1.65 (m, 2H), 2.73 (br s,4H), 3.29 (s, 3H), 3.34 (m, 2H), 3.60 (br s, 4H), 3.69 (m, 2H), 6.67 (d,1H), 7.19 (m, 3H), 7.38 (m, 3H), 7.77 (t, 1H). ESI-MS: m/z 438.2 (M+H)⁺.

Example 37(R)-1-Cyclohexyl-4-(3-methylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 1.15 (m, 6H), 1.59-1.79 (m,5H), 2.30 (m, 4H), 2.71 (dd, 1H), 2.88 (m, 1H), 3.11 (d, 1H), 3.57 (m,1H), 4.06 (m, 2H), 7.41 (m, 2H), 7.59 (m, 3H). ESI-MS: m/z 369.2 (M+H)⁺.

Example 381-Cyclohexyl-4-(3-methylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 1.03-1.28 (m, 6H) 1.49-1.89(m, 5H) 2.22-2.44 (m, 4H) 2.60-2.75 (m, 1H) 2.80-2.96 (m, 1H) 3.11 (d,J=12.88 Hz, 1H) 3.47-3.64 (m, 1H) 3.97-4.18 (m, 2H) 7.31-7.46 (m, 2H)7.51-7.66 (m, 3H) ESI-MS: m/z 369.30 (M+H)⁺.

Example 39(S)-1-Cyclohexyl-4-(3-methylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 1.16 (m, 6H), 1.59-1.79 (m,6H), 2.32 (m, 4H), 2.69 (dd, 1H), 2.89 (m, 1H), 3.11 (m, 1H), 3.57 (m,1H), 4.18 (m, 1H). ESI-MS: m/z 369.2 (M+H)⁺.

Example 401-Cyclohexyl-4-(3,5-dimethylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 0.93-1.32 (m, 11H) 1.45-1.93(m, 6H) 2.14-2.44 (m, 6H) 7.32-7.51 (m, 4H) 7.50-7.77 (m, 6H). ESI-MS:m/z 383.10 (M+H)⁺.

Example 411-Cyclohexyl-4-(2,5-dimethylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H NMR (400 MHz, MeOD) δ ppm 0.95-1.39 (m, 10H) 1.60 (br.s., 2H) 1.69-1.99 (m, 4H) 2.16-2.40 (m, 2H) 2.71-2.83 (m, 1H) 2.83-2.95(m, 1H) 3.04 (dd, J=14.65, 3.28 Hz, 1H) 3.38-3.67 (m, 2H) 7.29-7.46 (m,2H) 7.47-7.65 (m, 3H). ESI-MS: m/z 383.35 (M+H)⁺.

Example 425-(3-Chlorophenyl)-1-(3-(3-methoxypropoxy)phenyl)-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H (400 MHz, DMSO-d₆) δ ppm 0.86 (m, 1H), 1.25 (s, 2H),1.81-1.88 (m, J=6.32, 6.32, 6.32, 6.32 Hz, 2H), 2.33 (s, 3H), 3.16-3.22(m, 3H), 3.22 (s, 3H), 3.40 (t, J=6.19 Hz, 2H), 3.93 (t, J=6.32 Hz, 2H),6.67 (dd, J=7.83, 1.01 Hz, 1H), 6.79 (t, J=2.15 Hz, 1H), 6.86 (dd,J=8.08, 2.27 Hz, 1H), 6.95 (dt, J=7.39, 1.48 Hz, 1H), 7.11 (t, J=1.64Hz, 1H), 7.23 (t, J=8.08 Hz, 1H), 7.28-7.36 (m, 2H), 11.02 (s, 1H).ESI-MS: m/z 471.4 (M+H)⁺.

Example 435-(3-Chlorophenyl)-1-(3-(2-methoxyethoxy)phenyl)-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ¹H (400 MHz, DMSO-d₆) δ ppm 1.24 (s, 1H), 2.33 (s, 4H),3.21 (s, 4H), 3.27 (s, 3H), 3.57 (dd, J=3.79, 2.02 Hz, 2H), 4.00 (dd,J=5.18, 3.92 Hz, 2H), 6.69 (dd, J=7.83, 1.01 Hz, 1H), 6.80 (t, J=2.15Hz, 1H), 6.88 (dd, J=8.21, 2.15 Hz, 1H), 6.93-6.98 (m, 1H), 6.95 (d,J=7.33 Hz, 1H), 7.12 (t, J=1.64 Hz, 1H), 7.24 (t, J=8.08 Hz, 1H),7.29-7.37 (m, 2H), 11.03 (s, 1H). ESI-MS: m/z 457.3 (M+H)⁺.

Example 441-(1H-benzo[d]imidazol-2-yl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-6. ESI-MS: m/z 389.2 (M+H)⁺.

Example 451-Benzyl-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

According to the general procedure, Scheme A, Steps 1-5 and 7-8, thetitle compound was obtained as a yellow oil (83%). ¹H NMR (400 MHz,MeOD) δ ppm 2.7 (br s, 4H) 3.6 (br s, 4H), 5 (br, s, 2H), 7.10 (m, 2H)7.25 (m, 2H), 7.28-7.42 (m, 11H). ESI-MS: m/z 439.4 (M+H)⁺.

Example 461-Benzyl-4-phenyl-5-(piperazine-1-carbonyl)-3-(pyridin-2-yl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.74 (b, 4H), 3.43(b, 4H), 6.99 (m, 2H), 7.30 (m, 6H), 7.38 (m, 3H), 7.65 (d, 1H), 7.99(t, 1H), 8.34 (d, 1H), 8.48 (br s, 1H), 8.60 (br s, 1H). ESI-MS: m/z440.2 (M+H)⁺.

Example 471-((5-Methylisoxazol-3-yl)methyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 2.43 (s, 3H), 2.7 (brs, 4H) 3.6 (br s, 4H), 3.3 (2H), 5.18 (br s, 2H), 6.24 (s, 1H), 7.17 (m,4H) 7.37 (m, 6H). ESI-MS: m/z 444.4 (M+H)⁺.

Example 481-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)methyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 1.1 (m, 2H), 1.3 (m,2H), 2.4 (m, 1H), 2.9 (br s, 4H), 3.6 (br s, 4H), 5.5 (br s, 2H), 7.17(m, 4H) 7.37 (m, 6H). ESI-MS: m/z 487.4 (M+H)⁺.

Example 491-((1H-Imidazol-4-yl)methyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 2.9 (br s, 4H), 3.6(br s, 4H), 5.11 (br s, 2H), 7.17 (m, 4H) 7.38 (m, 6H), 7.63 (s, 1H),8.80 (s, 1H). ESI-MS: m/z 429.4 (M+H)⁺.

Example 501-((2-Aminothiazol-4-yl)methyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 2.9 (br s, 4H), 3.8(br s, 4H), 5.0 (br s, 2H), 7.17 (m, 5H) 7.38 (m, 6H). ESI-MS: m/z 461.3(M+H)⁺.

Example 511-(3-Fluorobenzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 2.6 (br s, 4H) 3.4(br s, 4H), 5.11 (br s, 2H), 7.06-7.43 (m, 14H). ESI-MS: m/z 457.3(M+H)⁺.

Example 521-(3,4-Difluorobenzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 2.8 (br s, 4H) 3.4(br s, 4H), 5.05 (br s, 2H), 7.1-7.43 (m, 13H). ESI-MS: m/z 475.4(M+H)⁺.

Example 531,5-Diphenyl-4-(piperazine-1-carbonyl)-3-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 1.37 (m, 2H), 1.62(m, 2H), 2.06 (m, 1H), 3.0 (m, 4H), 3.41 (t, 2H), 3.45 (m, 4H), 7.17 (m,4H) 7.38 (m, 6H). ESI-MS: m/z 447.4 (M+H)⁺.

Example 541-Methyl-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 2.7 (br s, 4H), 3.40(s, 3H), 3.6 (br s, 4H) 7.15 (m, 4H) 7.36 (m, 6H). ESI-MS: m/z 363.4(M+H)⁺.

Example 55(R)-4-(2-Benzylpiperazine-1-carbonyl)-3-methyl-1-(3-morpholinophenyl)-5-phenyl-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 2.4 (m, 2H), 2.6-3.2(m, 11H), 3.0 (s, 3H), 6.66 (m, 2H), 6.94 (m, 1H), 7.19-7.50 (m, 11H).ESI-MS: m/z 538.5 (M+H)⁺.

Example 561-Benzyl-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, DMSO-d6) δ ppm 2.99 (s, 4H), 3.67(s, 4H), 4.97 (br s, 2H), 6.62 (d, 1H), 6.77 (s, 1H), 6.89 (d, 1H), 7.05(m, 2H), 7.20 (t, 1H), 7.27-7.40 (m, 9H), 8.58 (br d, 2H). ESI-MS: m/z524.3 (M+H)⁺

Example 571-(3-(Morpholine-4-carbonyl)benzyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 3.03 (m, 4h), 3.44(br s, 2H), 3.63 (br s, 2H), 3.75 (m, 6H), 6.69 (m, 2H), 6.78 (m, 1H),6.94 (m, 1H), 7.14 (m, 2H), 7.26 (m, 1H), 7.35 (m, 5H), 7.52 (m, 3H).ESI-MS: m/z 637.3 (M+H)⁺.

Example 581-(3-Morpholinophenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-(3-(piperidine-1-carbonyl)benzyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 1.55-1.74 (br s,10H), 3.03 (m, 6H), 3.37 (m, 4H), 3.75 (m, 9H), 6.71 (m, 2H), 6.79 (m,1H), 6.97 (m, 1H), 7.14 (m, 2H), 7.25 (m, 1H), 7.31-7.42 (m, 6H),7.49-7.57 (m, 3H). ESI-MS: m/z 635.3 (M+H)⁺.

Example 592-(3-((3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)phenoxy)aceticacid

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 3.05 (m, 4H), 3.77(m, 4H), 3.98 (s, 2H), 4.75 (s, 2H), 6.71 (m, 1H), 6.82 (m, 2H), 6.88(m, 1H), 6.97 (m, 2H), 7.12 (m, 2H), 7.26 (t, 2H), 7.32 (m, 3H). ESI-MS:m/z 598.3 (M+H)⁺.

Example 601-Cyclohexyl-3-methyl-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 1.05-1.27 (m, 3H)1.61 (br. s., 1H) 1.64-1.88 (m, 4H) 2.21-2.45 (m, 3H) 3.32 (br. s., 1H)3.54 (br. s., 4H) 3.61 (dd, J=11.37, 7.83 Hz, 2H) 3.62-3.69 (m, 4H)7.26-7.44 (m, 2H) 7.46-7.70 (m, 3H). ESI-MS: m/z 369.30 (M+H)⁺.

Example 611-Isopropyl-3-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)urea

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ESI-MS: m/z 576.3 (M+H)⁺.

Example 621-Allyl-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 1.17 (d, J=7.83 Hz,3H) 1.47-2.00 (m, 6H) 2.33 (d, J=11.87 Hz, 3H) 2.66-3.22 (m, 2H)3.35-3.78 (m, 5H) 4.42 (d, J=4.29 Hz, 2H) 5.08 (d, J=17.18 Hz, 1H) 5.18(d, J=10.36 Hz, 1H) 5.73-5.97 (m, 1H) 7.23-7.46 (m, 2H) 7.47-7.71 (m,3H) 7.51-7.71 (m, 3H). ESI-MS: m/z 395.30 (M+H)⁺.

Example 632-(3-Cyclohexyl-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)acetamide

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 1.07-1.23 (m, 3H)1.60 (br. s., 1H) 1.68-1.88 (m, 4H) 2.21-2.40 (m, 2H) 2.86 (s, 2H) 3.00(s, 2H) 3.35 (s, 1H) 3.46 (br. s., 3H) 3.98 (s, 1H) 4.58 (br. s., 2H)7.28-7.46 (m, 2H) 7.50-7.67 (m, 3H). ESI-MS: m/z 412.30 (M+H)⁺.

Example 64(R)-1-Allyl-5-(2-benzylpiperazine-1-carbonyl)-3-cyclohexyl-4-phenyl-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 1.16 (br. s., 5H)1.61 (br. s., 3H) 1.82 (br. s., 4H) 2.31 (br. s., 4H) 3.54-3.72 (m, 2H)3.98 (s, 2H) 5.12 (br. s., 2H) 5.75 (br. s., 1H) 7.04-7.47 (m, 6H) 7.59(br. s., 4H). ESI-MS: m/z 485.40 (M+H)⁺.

Example 65(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-cyclohexyl-3-methyl-5-phenyl-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (br. s.,5H) 1.59 (br. s., 3H) 1.81 (br. s., 4H) 2.20-2.53 (m, 2H) 3.40-3.73 (m,6H) 3.99 (s, 3H) 7.28 (br. s., 6H) 7.54 (br. s., 4H). ESI-MS: m/z 459.40(M+H)⁺.

Example 66(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-cyclohexyl-3-(2-methoxyethyl)-5-phenyl-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96-1.22 (m,5H) 1.37-1.63 (m, 4H) 1.66-1.93 (m, 4H) 2.18-2.42 (m, 3H) 3.33-3.57 (m,8H) 3.96 (s, 2H) 7.26-7.40 (m, 6H) 7.41-7.58 (m, 4H). ESI-MS: m/z 503.40(M+H)⁺.

Example 67(R)-2-(5-(2-Benzylpiperazine-1-carbonyl)-3-cyclohexyl-2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)acetamide

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00-1.35 (m,5H) 1.48-1.98 (m, 5H) 2.22 (br. s., 2H) 2.98 (s, 2H) 3.08 (s, 2H) 3.79(s, 2H) 3.99 (s, 2H) 7.54 (br. s., 2H) 9.20 (br. s., 8H). ESI-MS: m/z502.3 (M+H)⁺.

Example 68 Methyl2-(3-cyclohexyl-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)-2-phenylacetate

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 1.05-1.45 (m, 4H)1.55-1.68 (m, 1H) 1.70-1.93 (m, 4H) 2.23-2.47 (m, 4H) 2.66-2.76 (m, 3H)3.08-3.30 (m, 2H) 3.56-3.78 (m, 2H) 7.27-7.42 (m, 6H) 7.48-7.64 (m, 4H).ESI-MS: m/z 503.30 (M+H)⁺.

Example 691-Cyclohexyl-5-phenyl-3-(1-phenylethyl)-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 1.01-1.42 (m, 4H)1.49-1.70 (m, 4H) 1.78 (d, J=14.91 Hz, 1H) 1.88-2.00 (m, 4H) 2.21-2.55(m, 4H) 2.68-3.07 (m, 2H) 3.52-3.81 (m, 2H) 5.60 (br. s., 2H) 7.24-7.35(m, 5H) 7.47-7.62 (m, 5H). ESI-MS: m/z 459.20 (M+H)⁺.

Example 70(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-cyclohexyl-3-methyl-5-phenyl-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (br. s.,5H) 1.59 (br. s., 3H) 1.81 (br. s., 4H) 2.20-2.53 (m, 2H) 3.40-3.73 (m,6H) 3.99 (s, 3H) 7.28 (br. s., 6H) 7.54 (br. s., 4H). ESI-MS: m/z 459.40(M+H)⁺.

Example 711-Cyclohexyl-3-phenethyl-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 0.96-1.47 (m, 6H)1.50-2.10 (m, 6H) 2.15-2.52 (m, 2H) 2.80-3.26 (m, 4H) 3.39-3.83 (m, 3H)4.04 (t, J=6.95 Hz, 2H) 7.04-7.43 (m, 6H) 7.47-7.74 (m, 4H). ESI-MS: m/z459.20 (M+H)⁺.

Example 721-(3-(1H-Pyrrol-1-yl)benzyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 1.03-1.42 (m, 5H)1.53-1.95 (m, 5H) 2.19-2.54 (m, 4H) 3.02-3.25 (m, 3H) 3.56-3.75 (m, 2H)4.97-5.14 (m, 2H) 6.23-6.34 (m, 2H) 7.17-7.23 (m, 2H) 7.31-7.37 (m, 2H)7.38-7.41 (m, 1H) 7.41-7.46 (m, 2H) 7.52-7.60 (m, 4H). ESI-MS: m/z510.20 (M+H)⁺.

Example 731-(3-(2-Phenoxyethoxy)benzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one

A. 1-Methyl-3-(2-phenoxyethoxy)benzene

To a solution of m-cresol (73B) (5.4 mL, 50 mmol) in EtOH (72 mL) wasadded aqueous 10M NaOH (2.14 g, 53.5 mmol), followed by 73A (7.59 g, 37mmol). The reaction mixture was refluxed for 24 hrs. The solvents wereremoved under reduced pressure. The residue was dissolved in ethylacetate, washed with 10% NaOH, and then filtered. The aqueous phase waswashed with saturated brine, dried over Na₂SO₄ and evaporated to givethe (73C) as white solid. ¹H-NMR: δ ppm 2.33 (s, 3H), 4.32 (s, 4H),6.78-7.30 (m, 9H).

B. 1-(Bromomethyl)-3-(2-phenoxyethoxy)benzene (73D)

To a solution of 73C (6.5 g, 28.5 mmol) and NBS (6.1 g, 28.5 mmol) indry CCl₄ (120 mL), catalytic amount of AIBN (0.46 g, 2.8 mmol) was addedand refluxed at 78° C. for 24 hrs. The hot solution was filtered and thefiltrate was concentrated under reduced pressure. The crude product waschromatographed over silica gel using a mixture of ethyl acetate and PEwhich gave (73D) as white powder. ¹H NMR (300 MHz, CDCl₃): δ ppm 4.33(s, 4H), 4.46 (s, 2H), 6.93-7.25 (m, 9H).

C.1-(3-(2-Phenoxyethoxy)benzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one(73F)

The title compound was prepared by the coupling of 73D to 73E followedby deprotection according to general procedure, Scheme A, Steps 7-8.ESI-MS: m/z 589.8 (M+H)⁺.

Example 741-(3-Morpholinophenyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 3.02 (m, 4H), 3.76(m, 4H), 5.1 (br s, 4H), 6.67 (dd, 1H), 6.74 (m, 1H), 6.95 (m, 3H), 7.01(m, 2H), 7.08 (m, 1H), 7.12 (m, 3H), 7.17 (m, 1H), 7.25 (t, 1H), 7.36(m, 6H). ESI-MS: m/z 616.3 (M+H)⁺.

Example 751-(3-(3-Methoxypropoxy)phenyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 1.95 (p, 2H), 3.34(s, 3H), 3.52 (t, 2H), 3.98 (t, 2H), 6.75 (m, 1H), 6.79 (m, 1H), 7.02(m, 3H), 7.04 (m, 2H), 7.13 (m, 1H), 7.15 (m, 2H), 7.20 (m, 1H), 7.28(t, 1H), 7.39 (m, 6H). ESI-MS: m/z 619.3 (M+H)⁺.

Example 761-(3-(Benzyloxy)benzyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 3.03 (m, 4H), 3.75(m, 4H), 6.75 (m, 2H), 6.89 (m, 1H), 6.97 (mm 4H), 7.10 (m, 2H),7.25-7.39 (m, 11H), 7.46 (m, 2H). ESI-MS: m/z 630.3 (M+H)⁺.

Example 771-(3-(1H-Pyrrol-1-yl)benzyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, MeOD) δ ppm 3.05 (m, 4H), 3.76(m, 4H), 6.31 (m, 2H), 6.73 (m, 1H), 6.79 (m, 1H), 6.96 (dd, 1H), 7.13(m, 2H), 7.24 (m, 4H), 7.34 (m, 3H), 7.47 (m, 3H). ESI-MS: m/z 589.3(M+H)⁺.

Example 78N-isobutyl-N-methyl-3-((3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)benzamide

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ESI-MS: m/z 637.4 (M+H)⁺.

Example 793-((2-oxo-3,4-diphenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)benzonitrile

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, CDCl₃-CD₃OD 10:1) δ ppm 7.52 (br.s., 1H) 7.43 (m, 2H) 7.33 (t, J=7.9 Hz, 1H) 7.09-7.18 (m, 6H) 6.96 (bt.J=6.3, 2.0 Hz, 2H) 6.85 (bdd. J=6.4, 1.5 Hz, 2H), 4.90 (bs. s., 1H) 2.95(m, 4H) 2.45 (m, 4H). ESI-MS: m/z 464.3 (M+H)⁺.

Example 80 Methyl3-((2-oxo-3,4-diphenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)benzoate

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, CDCl₃-CD₃OD 10:1) δ ppm 7.77 (dt,J=7.8, 1.3 Hz, 2H) 7.73 (t, J=1.5 Hz, 1H) 7.42 (ddd, J=7.7, 1.4, 1.3 Hz,3H) 7.29 (t, J=7.7 Hz, 1H) 7.07-7.18 (m, 6H) 6.96 (m, 1H) 6.84 (m, 1H)2.95 (bm, 4H) 2.45 (bm, 4H) 3.72 (s, 3H). ESI-MS: m/z 497.2 (M+H)⁺.

Example 811-Benzyl-4-phenyl-5-(piperazine-1-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46-1.78 (m, 2H)2.00 (s, 2H) 2.51-2.68 (m, 2H) 2.92-3.31 (m, 6H) 3.44-3.87 (m, 6H) 4.86(br. s., 1H) 7.17 (d, J=7.58 Hz, 2H) 7.22-7.41 (m, 5H) 7.46-7.63 (m, 3H)8.63 (br. s., 1H). ESI-MS: m/z 447.20 (M+H)⁺.

Example 821,5-Diphenyl-4-(piperazine-1-carbonyl)-3-(quinolin-8-ylmethyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, CDCl₃-CD₃OD 10:1) δ ppm 8.96 (dd,J=4.7, 1.6 Hz, 1H) 8.43 (dd, J=8.3, 1.5 Hz, 1H) 7.88 (d, J=8.8 Hz, 2H)7.61 (m, 2H) 7.15-7.26 (m, 25H) 7.04 (dd, J=8.0, 1.6 Hz, 1H) 6.89 (dd,J=8.0, 1.6, 1H) 5.57 (s, 1H). ESI-MS: m/z 490.2 (M+H)⁺.

Example 831-(3-methoxybenzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, CDCl₃-CD₃OD 10:1) δ ppm 7.01-7.17(m, 7H) 6.97 (d, J=7.1 Hz, 2H) 6.80 (dd, J=7.7, 1.4 Hz, 2H) 6.68-6.71(m, 2H) 6.71 (s, 2H) 6.63 (dd, J=8.2, 2.4 Hz, 3H) 5.13 (s, 1H) 4.53 (bs,1H) 3.61 (s., 3H) 3.17 (bs., 1H) 2.32 (bs., 2H) 2.22 (bs., 1H) 1.58 (bs,1H) 1.29 (bs, 1H). ESI-MS: m/z 469.2 (M+H)⁺.

Example 841-(Naphthalen-2-ylmethyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, CDCl₃-CD₃OD 10:1) δ ppm 7.67-7.76(m, 4H) 7.36-7.43 (m, 2H) 7.33 (dd, J=8.3, 1.8 Hz, 1H) 7.10-7.28 (m, 6H)7.09 (d, J=6.8 Hz, 2H) 6.88 (d, J=6.6 Hz, 2H). ESI-MS: m/z 489.2 (M+H)⁺.

Example 852-((2-Oxo-3,4-diphenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)benzonitrile

The title compound was prepared according to general procedure, SchemeA, Steps 1-5 and 7-8. ¹H NMR (400 MHz, CDCl₃-CD₃OD 10:1) δ ppm 7.60 (d,J=7.6 Hz, 1H) 7.46-7.56 (m, 3H) 7.34 (t, J=7.6 Hz, 1H) 7.17-7.29 (m, 5H)7.06 (bd, J=8.1 Hz, 2H) 6.94 (bd, J=6.8 Hz, 2H). ESI-MS: m/z 464.2(M+H)⁺.

Example 861-(3,5-Dimethoxybenzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, CDCl₃-CD₃OD 10:1) δ ppm 7.06-7.18 (m, 6H) 6.96 (d,J=6.6 Hz, 2H) 6.81 (d, J=6.2 Hz, 2H) 6.26 (d, J=2.0 Hz, 2H) 6.21 (t,J=2.1 Hz, 1H) 3.59 (s, 6H). ESI-MS: m/z 499.2 (M+H)⁺.

Example 871-(4-Chloro-3-(trifluoromethoxy)benzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ ppm 7.39 (d, J=8.3 Hz, 1H)7.17-7.27 (m, 8H) 7.03 (d, J=6.3 Hz, 2H) 6.93 (d, J=7.1 Hz, 2H) 4.96(bs, 1H). ESI-MS: m/z 557.2 (M+H)⁺.

Example 881-(3-(1H-Pyrrol-1-yl)benzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

¹H-NMR (400 MHz, CDCl₃-CD₃OD 10:1) δ ppm 7.05-7.34 (m, 14H) 6.90 (d,J=6.8 Hz, 2H) 6.25 (t, J=1.9 Hz, 2H). ESI-MS: m/z 504.2 (M+H)⁺.

Example 891-Cyclohexyl-4-(1,4-diazepane-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.40 (m, 3H) 7.17 (m., 2H) 3.03(m., 3H) 2.94 (m., 2H) 2.21 (m 2H) 1.87 (m 2H) 1.70 (m., 2H) 1.60 (m.,2H) 1.50 (m, 1H) 1.05 (m., 3H). ESI-MS: calc'd for C₂₁H₂₉N₄O₂, 369.2.found 469.2, (M+H)⁺.

Example 901-((2-Chloro-6-morpholinopyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, CDCl3-d) δ ppm 7.43 (m., 3H), 7.16 (m, 2H), 6.14, 6.30(s, 1H each), 4.79 (brs, 2H), 3.70 (t, J=4.6 Hz, 4H), 3.51 (m, 2H), 3.42(dd, J=5.3, 4.3 Hz, 4H), 3.38-3.46 (m, 1H), 3.25 (br. s., 3H), 2.24 (m,3H), 2.15-2.37 (m, 4H), 1.73 (d, J=11.6 Hz, 2H), 1.65 (d, J=11.7 Hz,2H), 1.52 (d, J=9.9 Hz, 1H), 1 1.04-1.16 (m, 4H). ESI-MS: calc'd forC₃₀H₃₈ClN₆O₃, 565.3. found 565.3. (M+H)⁺.

Example 911-Cyclohexyl-3-((2,6-di(1H-pyrazol-4-yl)pyridin-4-yl)methyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.18 (s, 4H), 7.43 (m, 3H), 7.31(s, 2H), 7.18 (m, 2H), 5.23 (s, 1H), 4.97 (br. s., 2H), 3.08 (m, 4H),2.34 (br. s., 1H), 2.28 (br. s., 2H), 2.19 (br. s., 2H), 1.77 (m, 2H),1.70 (m, 2H), 1.53 (m, 1H), 1.25-1.0 (m, 4H). ESI-MS: calc'd forC₃₂H₃₆N₉O₂, 578.3. found 578.3, (M+H)⁺.

Example 921-(1-Acetylpiperidin-3-yl)-3-(3-methoxybenzyl)-5-phenyl-4-(piperazine-1carbonyl)-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (d, J=10.11 Hz, 1H) 1.26-1.40 (m,1H) 1.67-1.78 (m, 2H) 1.89 (br. s., 2H) 1.97 (s, 3H) 2.32-2.42 (m, 2H)2.53-2.61 (m, 1H) 2.88-2.97 (m, 1H) 3.09 (br. s., 3H) 3.34 (t, J=11.37Hz, 1H) 3.40-3.50 (m, 2H) 3.63 (d, J=2.02 Hz, 2H) 4.28-4.35 (m, 1H) 4.54(br. s., 1H) 4.84 (br. s., 2H) 6.71-6.76 (m, 2H) 6.83-6.89 (m, 1H)7.22-7.39 (m, 3H) 7.48-7.58 (m, 3H) 8.55 (br. s., 1H). ESI-MS: m/z 518.5(M+H)⁺.

Example 931-(1-Acetylpiperidin-3-yl)-3-benzyl-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.09-1.22 (m, 1H) 1.24-1.39 (m, 1H)1.67-1.78 (m, 2H) 1.89 (br. s., 2H) 1.97 (s, 3H) 2.32-2.43 (m, 2H)2.89-2.96 (m, 2H) 2.99-3.11 (m, 2H) 3.34 (t, J=11.75 Hz, 2H) 3.40-3.52(m, 2H) 3.75 (d, J=13.39 Hz, 1H) 4.75-4.99 (m, 2H) 7.18 (t, J=6.95 Hz,2H) 7.25-7.42 (m, 5H) 7.46-7.58 (m, 3H) 8.45 (br. s., 1H). ESI-MS: m/z488.4 (M+H)⁺.

Example 941-(1-Acetylpiperidin-3-yl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04-1.16 (m, 1H) 1.20-1.36 (m, 1H)1.62-1.81 (m, 2H) 1.85 (s, 1H) 1.95 (s, 3H) 2.31-2.39 (m, 1H) 2.56-2.71(m, 3H) 2.88 (t, J=13.39 Hz, 1H) 3.24-3.34 (m, 2H) 3.67-3.87 (m, 2H)4.29 (d, J=12.63 Hz, 2H) 4.40 (d, J=8.59 Hz, 2H) 7.32 (dd, J=7.07, 2.27Hz, 1H) 7.38 (dd, J=7.20, 1.89 Hz, 1H) 7.46-7.57 (m, 2H) 8.59 (br. s.,1H) 10.76-10.84 (m, 1H). ESI-MS: m/z 398.4 (M+H)⁺.

Example 951-(1-Benzoylpiperidin-3-yl)-3-benzyl-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25-1.45 (m, 1H) 1.58-1.97 (m, 3H)2.31-2.35 (m, 1H) 2.57-2.69 (m, 4H) 2.90-3.20 (m, 6H) 3.80-3.93 (m, 1H)4.42 (br. s., 1H) 4.75-5.00 (m, 2H) 7.02-7.22 (m, 4H) 7.23-7.49 (m, 8H)7.54 (br. s., 3H) 8.40 (br. s., 1H). ESI-MS: m/z 550.4 (M+H)⁺.

Example 961-Benzyl-4-phenyl-3-(1-(phenylsulfonyl)piperidin-3-yl)-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 550.4 (M+H)⁺.

Example 971-Benzyl-3-(1-(furan-2-carbonyl)piperidin-3-yl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34 (dd, J=22.61, 10.48 Hz, 2H) 1.79(d, J=11.37 Hz, 3H) 2.12-2.38 (m, 2H) 2.65 (dd, J=22.74, 7.83 Hz, 3H)2.93-3.20 (m, 3H) 3.53-3.66 (m, 3H) 4.28 (d, J=12.38 Hz, 2H) 4.84 (d,J=127.07 Hz, 2H) 6.60 (br. s., 1H) 6.96 (br. s., 1H) 7.14-7.36 (m, 7H)7.45 (br. s., 3H) 7.82 (br. s., 1H). ESI-MS: m/z 540.4 (M+H)⁺.

Example 985-Phenyl-1-(1-(phenylsulfonyl)piperidin-3-yl)-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14-1.22 (m, 1H) 1.26-1.44 (m, 1H) 1.74(d, J=10.61 Hz, 2H) 2.09 (t, J=11.24 Hz, 1H) 2.16-2.31 (m, 4H) 2.96 (t,J=10.99 Hz, 1H) 3.09 (br. s., 4H) 3.51-3.70 (m, 4H) 7.24-7.33 (m, 2H)7.46-7.56 (m, 3H) 7.63 (t, J=7.71 Hz, 2H) 7.68-7.77 (m, 3H) 10.66 (br.s., 1H). ESI-MS: m/z 496.4 (M+H)⁺.

Example 991-(1-Acetylpiperidin-3-yl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22-1.40 (m, 1H) 1.64-1.78 (m, 2H) 1.97(br. s., 2H) 1.99 (s, 3H) 2.14 (br. s., 2H) 2.30-2.41 (m, 1H) 2.58-2.70(m, 1H) 2.90 (t, J=12.25 Hz, 1H) 2.98-3.14 (m, 1H) 3.20-3.31 (m, 1H)3.39-3.50 (m, 1H) 3.73 (d, J=13.64 Hz, 1H) 4.31 (d, J=12.13 Hz, 1H)4.64-5.02 (m, 2H) 6.64-6.79 (m, 2H) 6.86-6.95 (m, 2H) 6.99 (dd, J=7.96,2.40 Hz, 2H) 7.14-7.26 (m, 2H) 7.28-7.37 (m, 2H) 7.38-7.55 (m, 5H).ESI-MS: m/z 580.4 (M+H)⁺.

Example 1001-Benzyl-4-phenyl-3-(1-(phenylsulfonyl)piperidin-3-yl)-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25-1.50 (m, 2H) 1.66-1.84 (m, 2H)2.04-2.37 (m, 5H) 2.55-2.69 (m, 1H) 2.81-3.22 (m, 4H) 3.30 (s, 2H)3.58-3.72 (m, 2H) 4.51-5.01 (m, 2H) 7.12 (d, J=7.07 Hz, 2H) 7.23-7.36(m, 5H) 7.46-7.54 (m, 3H) 7.56-7.83 (m, 5H). ESI-MS: m/z 586.4 (M+H)⁺.

Example 1011-Benzyl-4-phenyl-5-(piperazine-1-carbonyl)-3-(1-(pyridin-2-ylsulfonyl)piperidin-3-yl)-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00-1.43 (m, 4H) 1.46-1.82 (m, 4H)2.23-2.39 (m, 4H) 2.52-2.67 (m, 2H) 2.88-3.12 (m, 2H) 3.38-3.76 (m, 4H)4.31-5.14 (m, 2H) 6.81-7.52 (m, 8H) 7.68 (br. s., 1H) 8.00 (d, J=71.24Hz, 2H) 8.64 (br. s., 1H). ESI-MS: m/z 587.5 (M+H)⁺.

Example 1021-(3-Phenoxybenzyl)-4-phenyl-3-(1-(phenylsulfonyl)piperidin-3-yl)-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25-1.45 (m, 2H) 1.69-1.84 (m, 2H)2.06-2.28 (m, 5H) 2.28-2.36 (m, 1H) 2.58-2.69 (m, 1H) 2.92-3.19 (m, 4H)3.30 (s, 1H) 3.56-3.67 (m, 3H) 4.59-4.96 (m, 2H) 6.67 (s, 1H) 6.88 (dd,J=7.83, 2.02 Hz, 1H) 6.98 (d, J=7.83 Hz, 2H) 7.18 (t, J=7.33 Hz, 1H)7.22-7.27 (m, 2H) 7.32 (t, J=7.83 Hz, 1H) 7.41 (t, J=7.83 Hz, 2H)7.48-7.56 (m, 3H) 7.63 (br. s., 2H) 7.72 (d, J=6.57 Hz, 3H). ESI-MS: m/z678.4 (M+H)⁺.

Example 1031-(3-Phenoxybenzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-(1-(pyridin-2-ylsulfonyl)piperidin-3-yl)-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22-1.36 (m, 2H) 1.67-1.80 (m, 2H) 2.27(br. s., 2H) 2.55-2.69 (m, 2H) 2.90-3.16 (m, 2H) 3.27-3.30 (m, 2H)3.44-3.55 (m, 2H) 3.53-3.74 (m, 4H) 4.62-4.95 (m, 2H) 6.65 (s, 1H)6.85-6.93 (m, 2H) 6.98 (d, J=8.08 Hz, 2H) 7.10-7.26 (m, 3H) 7.32 (t,J=7.96 Hz, 1H) 7.41 (t, J=7.96 Hz, 2H) 7.48-7.57 (m, 3H) 7.69 (br. s.,1H) 7.92 (br. s., 1H) 8.10 (br. s., 1H) 8.64 (br. s., 1H). ESI-MS: m/z679.4 (M+H)⁺.

Example 1041-(1-Acetylpiperidin-3-yl)-4-((R)-2-benzylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06-1.16 (m, 1H) 1.24-1.38 (m, 1H)1.76-1.83 (m, 2H) 1.94 (s, 3H) 2.08 (dd, J=13.64, 6.06 Hz, 1H) 2.29-2.39(m, 1H) 2.64-2.76 (m, 1H) 2.85-3.08 (m, 2H) 3.25-3.39 (m, 2H) 3.68-3.78(m, 1H) 3.83-3.94 (m, 1H) 4.25-4.38 (m, 2H) 4.43-4.58 (m, 2H) 7.15-7.36(m, 7H) 7.42-7.53 (m, 3H) 8.77 (d, J=52.80 Hz, 2H) 10.68 (br. s., 1H).ESI-MS: m/z 488.4 (M+H)⁺.

Example 1051-Benzyl-3-((1R,2R)-2-hydroxycyclohexyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.90-1.10 (m, 4H) 1.21-1.28 (m, 2H)1.52-1.75 (m, 4H) 1.76-1.95 (m, 2H) 2.09-2.45 (m, 6H) 2.90-3.20 (m, 2H)4.20-4.49 (m, 2H) 4.58-5.16 (m, 2H) 7.12-7.57 (m, 8H). ESI-MS: m/z 461.4(M+H)⁺.

Example 1061-((1R,2R)-2-Hydroxycyclohexyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.92-1.11 (m, 4H) 1.19-1.27 (m, 2H)1.53-1.76 (m, 4H) 1.83-1.92 (m, 3H) 2.07-2.42 (m, 4H) 2.87-3.15 (m, 2H)4.30 (d, J=11.87 Hz, 1H) 4.58-5.05 (m, 2H) 6.74-6.83 (m, 1H) 6.86 (d,J=8.34 Hz, 1H) 6.93 (d, J=7.58 Hz, 1H) 6.98 (d, J=8.59 Hz, 2H) 7.16 (t,J=7.45 Hz, 1H) 7.28-7.51 (m, 8H). ESI-MS: m/z 553.4 (M+H)⁺.

Example 107N—(((S)-1-(1-((1R,2R)-2-Hydroxycyclohexyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazin-2-yl)methyl)benzamide

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.81-0.88 (m, 1H) 1.10-1.29 (m, 4H)1.49-1.67 (m, 4H) 1.91 (dd, J=6.95, 3.92 Hz, 1H) 1.95-2.07 (m, 1H)2.20-2.34 (m, 2H) 2.57-2.69 (m, 2H) 3.08-3.17 (m, 1H) 3.45-3.65 (m, 2H)4.25-4.44 (m, 2H) 5.01 (d, J=3.79 Hz, 1H) 7.35-7.56 (m, 8H) 7.79 (d,J=7.33 Hz, 2H) 8.49 (t, J=5.18 Hz, 1H) 10.43 (br. s., 1H). ESI-MS: m/z504.4 (M+H)⁺.

Example 108(S)—N-((1-(1-Cyclohexyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazin-2-yl)methyl)benzamide

¹H NMR (400 MHz, MeOD) δ ppm 1.17 (m, 3H), 1.31 (m, 1H), 1.60 (m, 2H),1.82 (m, 4H), 2.72 (m, 3H), 3.05-3.28 (m, 4H), 3.45-3.57 (m, 3H), 7.41(m, 2H), 7.47 (m, 2H), 7.59 (m, 4H), 7.79 (m, 2H). ESI-MS: m/z 488.3(M+H)⁺.

Example 109(R)-4-(2-Benzylpiperazine-1-carbonyl)-1,5-diphenyl-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, MeOD) d ppm 2.5 (m, 2H), 2.6-3.5 (m, 7H), 7.15 (m, 4H),7.36 (m, 6H); ESI-MS: m/z 439.3 (M+H)⁺.

Example 110(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(3-morpholinophenyl)-5-phenyl-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, MeOD) d ppm 2.78 (m, 1H), 2.96 (br s, 4H), 3.0 (t, 4.8Hz, 4H), 3.21 (br s, 2H), 3.74 (t, 4.8 Hz, 4H), 6.60 (m, 2H), 6.93 (m,1H), 7.12-7.42 (m, 11H); ESI-MS: m/z 524.4 (M+H)⁺.

Example 111(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-cyclohexyl-5-phenyl-1H-imidazol-2(3H)-one

¹H NMR (400 MHz, MeOD) d ppm 1.04-1.31 (m, 4H) 1.44-1.70 (m, 4H)2.65-2.87 (m, 2H) 2.86-3.06 (m, 4H) 3.05-3.25 (m, 4H) 3.42-3.61 (m, 2H)7.13 (dd, J=6.95, 1.89 Hz, 2H) 7.21-7.45 (m, 5H) 7.51-7.70 (m, 3H)ESI-MS: m/z 445.2 (M+H)⁺.

Example 112(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(2,3-dimethoxyphenyl)-5-phenyl-1H-imidazol-2(3H)-one

Example 113(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(2-methoxyphenyl)-5-phenyl-1H-imidazol-2(3H)-one

Example 114(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(3-(methylsulfonyl)phenyl)-5-phenyl-1H-imidazol-2(3H)-one

Example 1151-(1-Acetylpiperidin-3-yl)-4-((R)-2-benzylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one

ESI-MS: m/z 488.3 (M+H)⁺.

Example 116(R)-4-(2-Benzylpiperazine-1-carbonyl)-5-phenyl-1-o-tolyl-1H-imidazol-2(3H)-one

ESI-MS: m/z 453.02 (M+H)⁺.

Example 117(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(2-nitrophenyl)-5-phenyl-1H-imidazol-2(3H)-one

ESI-MS: m/z 484.03 (M+H)⁺.

Example 118(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)methanesulfonamide

ESI-MS: m/z 532.05 (M+H)⁺.

Example 119(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)propane-1-sulfonamide

ESI-MS: m/z 560.09 (M+H)⁺.

Example 120(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)cyclopropanecarboxamide

ESI-MS: m/z 522.10 (M+H)⁺.

Example 121(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)butyramide

ESI-MS: m/z 524.11 (M+H)⁺.

Example 122(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)acetamide

ESI-MS: m/z 496.06 (M+H)⁺.

Example 123(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)cyclopropanesulfonamide

ESI-MS: m/z 558.06 (M+H)⁺.

Example 124(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)benzamide

ESI-MS: m/z 558.11 (M+H)⁺.

Example 125(R)—N-(2-(4-(2-benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)Benzenesulfonamide

ESI-MS: m/z 594.05 (M+H)⁺.

Example 1264-((R)-2-Benzylpiperazine-1-carbonyl)-1-((1S,2S)-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-2(3H)-one

ESI-MS: m/z 461.09 (M+H)⁺.

Example 127(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)ethanesulfonamide

Example 128(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)butane-1-sulfonamide

Example 129(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)prop-2-ene-1-sulfonamide

ESI-MS: m/z 558.12 (M+H)⁺.

Example 130(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-((1-hydroxycyclohexyl)methyl)-5-phenyl-1H-imidazol-2(3H)-one

ESI-MS: m/z 475.15 (M+H)⁺.

Example 131(R)-4-(2-Benzylpiperazine-1-carbonyl)-5-phenyl-1-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 550.1 (M+H)⁺.

Example 132(R)-4-(2-Benzylpiperazine-1-carbonyl)-5-phenyl-1-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 494.1 (M+H)⁺.

Example 133(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(1-butyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-cyclopropyl-1H-imidazol-2(3H)-one

ESI-MS: m/z 514.19 (M+H)⁺.

Example 134(R)-4-(2-Benzylpiperazine-1-carbonyl)-5-cyclopropyl-1-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 458.11 (M+H)⁺.

Example 135(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-phenyl-1H-imidazol-2(3H)-one

Example 136(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(indolin-6-yl)-5-phenyl-1H-imidazol-2(3H)-one

ESI-MS: m/z 480.1 (M+H)⁺.

Example 137(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(4-(2-methoxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-phenyl-1H-imidazol-2(3H)-one

ESI-MS: m/z 554.1 (M+H)⁺.

Example 1384-((R)-2-Benzylpiperazine-1-carbonyl)-1-(3-methoxy-2,3-dihydro-1H-inden-5-yl)-5-phenyl-1H-imidazol-2(3H)-one

ESI-MS: m/z 509.2 (M+H)⁺.

Example 139 (R)-Ethyl6-(4-(2-benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)indoline-1-carboxylate

ESI-MS: m/z 552.11 (M+H)⁺.

Example 140(R)-4-(2-(2-Phenoxyethyl)piperazine-1-carbonyl)-5-phenyl-1-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 524.10 (M+H)⁺.

Example 1411-Allyl-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one

ESI-MS: m/z 403.2 (M+H)⁺.

Example 1421-(3-Phenoxybenzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one

ESI-MS: m/z 545.2 (M+H)⁺.

Example 1431-(3-Methoxybenzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one

ESI-MS: m/z 483.2 (M+H)⁺.

Example 1441-(3,4-Difluorobenzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one

ESI-MS: m/z 489.1 (M+H)⁺.

Example 1451-Allyl-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 419.1 (M+H)⁺.

Example 1461-(2-Methoxyphenyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 561.2 (M+H)⁺.

Example 1471-(3-Methoxybenzyl)-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 499.1 (M+H)⁺.

Example 1481-(3,4-Difluorobenzyl)-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 505.1 (M+H)⁺.

Example 1491-(3-(2-Phenoxyethoxy)benzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one

ESI-MS: m/z 589.8 (M+H)⁺.

Example 1501-Allyl-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 474.2 (M+H)⁺.

Example 1511-(3-Methoxybenzyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 554.2 (M+H)⁺.

Example 1521-((1S,2R)-2-Hydroxycyclohexyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 553.1 (M+H)⁺.

Example 1531-((1S,2R)-2-Hydroxycyclohexyl)-3-(3-methoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 491.1 (M+H)⁺.

Example 1541-(3,4-Difluorobenzyl)-3-((1S,2R)-2-hydroxycyclohexyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 497.1 (M+H)⁺.

Example 155N-(2-(2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide

ESI-MS: m/z 546.1 (M+H)⁺.

Example 156N-(3-(2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide

ESI-MS: m/z 524.2 (M+H)⁺.

Example 1571-(Cyclohexylmethyl)-3-((1S,2R)-2-hydroxycyclohexyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 467.3 (M+H)⁺.

Example 158N-(2-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide

ESI-MS: m/z 562.2 (M+H)⁺.

Example 159N-(3-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide

ESI-MS: m/z 562.2 (M+H)⁺.

Example 1601-(Cyclohexylmethyl)-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 475.2 (M+H)⁺.

Example 161N-(3-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

ESI-MS: m/z 576.2 (M+H)⁺.

Example 162N-(3-(2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

ESI-MS: m/z 560.2 (M+H)⁺.

Example 1631-(Cyclohexylmethyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one

ESI-MS: m/z 459.1 (M+H)⁺.

Example 1641-(3,4-Difluorobenzyl)-3-(3-(3-methoxypropoxy)phenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 459.1 (M+H)⁺.

Example 1653-Methyl-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)butanamide

ESI-MS: m/z 504.2 (M+H)⁺.

Example 166N-(2-(2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide

ESI-MS: m/z 510.1 (M+H)⁺.

Example 167N-(3-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)-3-methylbutanamide

ESI-MS: m/z 520.2 (M+H)⁺.

Example 168N-(2-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide

ESI-MS: m/z 526.2 (M+H)⁺.

Example 169N-(2-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)-3-methylbutanamide

ESI-MS: m/z 506.2 (M+H)⁺.

Example 170N-(3-(3-((2S)-2-Hydroxycyclohexyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide

ESI-MS: m/z 532.3 (M+H)⁺.

Example 171N-(3-(3-((2S)-2-Hydroxycyclohexyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

ESI-MS: m/z 506.2 (M+H)⁺.

Example 172N-(3-(3-((2S)-2-Hydroxycyclohexyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)-3-methylbutanamide

ESI-MS: m/z 512.2 (M+H)⁺.

Example 173N-(2-(3-((2S)-2-Hydroxycyclohexyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)-3-methylbutanamide

ESI-MS: m/z 498.2 (M+H)⁺.

Example 174N-(3-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazolidin-1-yl)propyl)benzamide

ESI-MS: m/z 595.2 (M+H)⁺.

Example 175N-(3-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

ESI-MS: m/z 631.2 (M+H)⁺.

Example 1763-Methyl-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)butanamide

ESI-MS: m/z 575.3 (M+H)⁺.

Example 177N-(2-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide

ESI-MS: m/z 581.3 (M+H)⁺.

Example 1783-Methyl-N-(2-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)butanamide

ESI-MS: m/z 561.3 (M+H)⁺.

Example 179N-(3-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide

ESI-MS: m/z 598.3 (M+H)⁺.

Example 180N-(3-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

ESI-MS: m/z 634.2 (M+H)⁺.

Example 181N-(3-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)-3-methylbutanamide

ESI-MS: m/z 578.3 (M+H)⁺.

Example 182N-(2-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide

ESI-MS: m/z 584.3 (M+H)⁺.

Example 183N-(2-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide

ESI-MS: m/z 620.2 (M+H)⁺.

Example 184N-(2-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)-3-methylbutanamide

ESI-MS: m/z 564.3 (M+H)⁺.

Example 185N-(2-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide

ESI-MS: m/z 617.2 (M+H)⁺.

Example 1861-(3-(2-Methoxyethoxy)benzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one

ESI-MS: m/z 527.2 (M+H)⁺.

Example 1871-(3-(2-Methoxyethoxy)benzyl)-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 543.2 (M+H)⁺.

Example 1881-(2-Methoxyphenyl)-3-(3-(2-phenoxyethoxy)benzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 605.3 (M+H)⁺.

Example 1891-(Cyclohexylmethyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 530.2 (M+H)⁺.

Example 1901-(3,4-Difluorobenzyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 560.2 (M+H)⁺.

Example 1911-(3-Morpholinophenyl)-3-(3-(2-phenoxyethoxy)benzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 660.3 (M+H)⁺.

Example 1921-(3-(2-Methoxyethoxy)benzyl)-3-(3-(3-methoxypropoxy)phenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one

ESI-MS: m/z 601.3 (M+H)⁺.

Example 1932-Fluoro-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

ESI-MS: m/z 649.2 (M+H)⁺.

Example 1942-Chloro-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

ESI-MS: m/z 665.2 (M+H)⁺.

Example 1953-Chloro-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

ESI-MS: m/z 665.2 (M+H)⁺.

Example 196N-(3-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)propane-2-sulfonamide

ESI-MS: m/z 597.3 (M+H)⁺.

Example 1972-Methyl-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

ESI-MS: m/z 645.3 (M+H)⁺.

Example 1983-Methoxy-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

ESI-MS: m/z 661.2 (M+H)⁺.

Example 1994-Methoxy-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

ESI-MS: m/z 661.2 (M+H)⁺.

Example 2001-(3-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)-3-phenylurea

ESI-MS: m/z 610.2 (M+H)⁺.

Example 201 General procedure for the preparation of tert-Butyl4-(3-(3-aminopropyl)-2-oxo-5-phenyl-1-o-tolyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate(201) and other imidazolone analogs

A. 1-Azido-3-iodopropane (201A)

NaN3 (13.0 g, 0.2 mol) was added to a solution of1-bromo-3-chloropropane (201A) (19.7 mL, 0.2 mol) in 500 mL of DMF atroom temperature. The reaction mixture was allowed to stir for 24 hrs.The reaction mixture was partitioned between ether and water, and theorganic layer was washed with water 3×, dried over Na₂SO₄ andconcentrated to give 1-azido-3-chloropropane (201B) as a light yellowoil, which was carried into next reaction without further purification.¹H-NMR (300 MHz, CDCl₃): δ ppm 2.03 (m, 2H), 3.51 (t, 2H, J=6.6 Hz),3.65 (t, 2H, J=6.6 Hz).

NaI (59.9 g, 400 mmol) was added to a solution of 201B (˜200 mmol) in600 mL of acetone and heated to reflux for 24 h. The reaction mixturewas partitioned between EtOAc and water. Aqueous layer was extractedwith EtOAc (3×100 mL). The combined organic layers were dried overNa₂SO₄ and concentrated to give an oil. Flash chromatography (5%,EtOAc/hexane) afforded 1-azido-3-iodopropane (201C) (23 g, 55%, twosteps) as a yellow oil. ¹H-NMR (300 MHz, CDCl₃): δ ppm 2.08 (m, 2H),3.27 (t, 2H, J=6.9 Hz), 3.46 (t, 2H, J=6.6 Hz).

B. tert-Butyl4-(3-(3-aminopropyl)-2-oxo-5-phenyl-1-o-tolyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazine-1-carboxylate(201)

To a solution of 201D (324 mg, 0.7 mmol) in 5 mL DMF was added NaH (30mg, 0.74 mmol). The reaction mixture was stirred at RT for 30 mins. 201C(155 mg, 0.74 mmol) was added to the reaction mixture; the resultingmixture was stirred at RT overnight. The mixture was diluted with ethylacetate and H₂O. The aqueous phase was extracted with ethyl acetate; thecombined organic phase was washed with water, dried with anhydrousMgSO₄, filtered, and concentrated in vacuo, leaving a yellow oil whichwas purified by flash chromatography (elution: PE/EA=10/1˜0/1) giving201E, (264 mg, 69%) as a light yellow solid. LCMS: purity=100% MS (EZ,m/e): 546 (M+H)⁺.

A mixture of 201E (260 mg, 0.48 mmol) and triphenylphosphine (137 mg,0.52 mmol) in THF (wet, 10 mL) was stirred at RT overnight. The mixturewas concentrated in vacuo, and the residue was purified by flashchromatography, and afforded 201, (184 mg, 74%), as a white solid. LCMS:purity=99%. (MS (EZ, m/e:) 520(M+H)⁺.

C.N-(3-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide(162)

To a stirred solution of 201 (31 mg, 0.059 mmol) and DIPEA (11.5 mg) inTHF (3 mL) was added benzenesulfonyl chloride (15.7 mg, 0.089 mmol) at0° C. The reaction mixture was warmed to RT overnight, then extractedwith ethyl acetate. The organic phase was washed with water, dried withanhydrous MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by flash chromatography, afforded 201G, (17 mg, 44%), as alight yellow solid. ¹H NMR (300 MHz, CDCl3) δ ppm 1.27 (s, 9H), 1.96 (m,2H), 2.03 (s, 3H), 3.0 (m, 4H), 3.2-3.5 (m, 4H), 3.8-4.2 (m, 4H), 6.9(m, 2H), 7.25 (m, 6H), 7.44 (m, 4H), 7.85 (m, 2H); ESI-MS: m/z 660.2(M+H)⁺.

The protected group of 201G was removed by stirring in 20% TFA-DCM andstirred for 30 mins to 24 hrs at room temperature (Scheme A, Step 8)which afforded the title compound 162, after purified by RP-HPLC, as TFAsalt. ESI-MS: m/z 560.2 (M+H)⁺.

D.1-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)-3-phenylurea(223)

To a solution of 201 (27 mg, 0.05 mmol) in CH₂Cl₂ (1 mL), which wasstirred at room temperature and was added phenyl isocyanate (6.5 mg,0.055 mmol). The reaction mixture was stirred for 1.5 hours at 30° C.,and was evaporated under reduced pressure. The residue was purified byflash chromatography, afforded 201H (21 mg) as a white solid. LCMS:purity=96%. MS (EZ, m/e): 639.2 (M+H)⁺.

The protected group of 201H was removed by stirring in 20% TFA-DCM for30 mins to 24 hrs at room temperature (Scheme A, Step 8) which affordedthe title compound 223, after purified by RP-HPLC, as TFA salt. ESI-MS:m/z 539.2 (M+H)⁺

E.N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide(156)

To a stirred solution of 201 (31 mg, 0.059 mmol) and DIPEA (11.5 mg) inTHF (3 mL) was added benzoyl chloride (12.5 mg, 0.089 mmol) at 0° C. Thereaction mixture was warmed to RT overnight, then extracted with ethylacetate. The organic phase was washed with water, dried with anhydrousMgSO₄, filtered, and concentrated in vacuo. The residue was purified byflash chromatography, afforded 201I, (16 mg, 43%) as a light yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ ppm 1.27 (s, 9H), 1.9 (m, 2H), 2.03 (s,3H), 3.2 (m, 4H), 3.4 (m, 4H), 4.1 (m, 4H), 7.0 (m, 2H), 7.25 (m, 6H),7.43 (m, 4H), 7.91 (m, 2H); ESI-MS: m/z 624.2 (M+H)⁺.

The protected group of 201I was removed by stirring in 20% TFA-DCM for30 mins to 24 hrs at room temperature (Scheme A, Step 8) which affordedthe title compounds 156, after purified by RP-HPLC, as TFA salt. ESI-MS:m/z 524.2 (M+H)⁺.

F. Phenyl3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propylcarbamate(252)

To a stirred solution of 201F (52 mg, 0.1 mmol) and DIPEA (54 mL, 3 eq)in THF (3 mL) was added phenyl carbonochloridate (18.8 mg, 15.1 mL, 0.12mmol) at 0° C. The reaction mixture was warmed to RT overnight, thenextracted with ethyl acetate. The organic phase was washed with water,dried with anhydrous MgSO₄, filtered, and concentrated in vacuo. Theresidue was purified by flash chromatography to afford 201J (17 mg 27%)as a light yellow solid. ESI-MS: m/z 640.3 (M+H)⁺.

The protected group of 201J was removed by stirring in 20% TFA-DCM for30 mins to 24 hrs at room temperature (Scheme A, Step 8) which affordedthe title compound 252, after purified by RP-HPLC, as TFA salt. ESI-MS:m/z 540.3 (M+H)⁺.

Example 2024-Chloro-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 666.2 (M+H)⁺.

Example 2032-Fluoro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 564.2 (M+H)⁺.

Example 2042-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 581.2 (M+H)⁺.

Example 2053-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 581.2 (M+H)⁺.

Example 207N-(2-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)propane-2-sulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 581.2 (M+H)⁺.

Example 2074-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 512.2 (M+H)⁺.

Example 2082-Methyl-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 560.2 (M+H)⁺.

Example 2093-Methoxy-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 576.2 (M+H)⁺.

Example 2104-Methoxy-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 576.2 (M+H)⁺.

Example 2111-(2-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)-3-phenylurea

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 525.3 (M+H)⁺.

Example 2121-(2-Chlorophenyl)-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 560.3 (M+H)⁺.

Example 2131-(4-Chlorophenyl)-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 560.2 (M+H)⁺.

Example 2141-(2-Methoxyphenyl)-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 555.3 (M+H)⁺.

Example 2151-(3-Methoxyphenyl)-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 555.3 (M+H)⁺.

Example 2161-Isopropyl-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 491.3 (M+H)⁺.

Example 2172-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 595.2 (M+H)⁺.

Example 2183-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 595.2 (M+H)⁺.

Example 2194-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 595.3 (M+H)⁺.

Example 2202-Methyl-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 574.3 (M+H)⁺.

Example 2213-Methoxy-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 590.3 (M+H)⁺.

Example 2224-Methoxy-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 590.3 (M+H)⁺.

Example 2231-(3-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)-3-phenylurea

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 539.3 (M+H)⁺.

Example 2241-(2-Chlorophenyl)-3-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)urea

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 574.3 (M+H)⁺.

Example 2251-(2-Methoxyphenyl)-3-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)urea

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 569.3 (M+H)⁺.

Example 2261-(3-Methoxyphenyl)-3-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)urea

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 569.3 (M+H)⁺.

Example 2271-Isopropyl-3-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)urea

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 505.4 (M+H)⁺.

Example 2281-(4-Methoxyphenyl)-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 555.3 (M+H)⁺.

Example 2292-Fluoro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 578.2 (M+H)⁺.

Example 2302-Fluoro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 528.3 (M+H)⁺.

Example 2312-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 545.3 (M+H)⁺.

Example 2323-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 545.2 (M+H)⁺.

Example 2334-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 545.2 (M+H)⁺.

Example 2342-Methoxy-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 540.3 (M+H)⁺.

Example 2354-Methoxy-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 540.3 (M+H)⁺.

Example 236N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)isobutyramide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 476.4 (M+H)⁺.

Example 237N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)cyclohexanecarboxamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 516.4 (M+H)⁺.

Example 2383-Methyl-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)butanamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 590.3 (M+H)⁺.

Example 239N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)propane-2-sulfonamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 526.3 (M+H)⁺.

Example 2402-Fluoro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 542.3 (M+H)⁺.

Example 2412-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 559.2 (M+H)⁺.

Example 2423-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 559.3 (M+H)⁺.

Example 2434-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 559.3 (M+H)⁺.

Example 2442-Methoxy-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 554.3 (M+H)⁺.

Example 2454-Methoxy-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 554.3 (M+H)⁺.

Example 246N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)isobutyramide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 490.3 (M+H)⁺.

Example 247N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)cyclohexanecarboxamide

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 530.3 (M+H)⁺.

Example 248 Phenyl2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethylcarbamate

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 526.2 (M+H)⁺.

Example 249 Methyl2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethylcarbamate

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 464.2 (M+H)⁺.

Example 250 Ethyl2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethylcarbamate

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 478.3 (M+H)⁺.

Example 251 Benzyl2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethylcarbamate

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 540.3 (M+H)⁺.

Example 252 Phenyl3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propylcarbamate

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 540.3 (M+H)⁺.

Example 253 Methyl3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propylcarbamate

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 478.2 (M+H)⁺.

Example 254 Ethyl3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propylcarbamate

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 492.3 (M+H)⁺.

Example 255 Benzyl3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propylcarbamate

The titled compound was prepared by a procedure analogous to thatdescribed in Example 201. ESI-MS: m/z 554.3 (M+H)⁺.

In addition to the examples described above, the following non-limitinggroup of compounds can be prepared utilizing the above reaction schemes,and variations thereof, with the appropriate selection of substituents.

BIOLOGICAL EXAMPLES Example A Expression of Preprorenin and Purificationof Prorenin

The sequence of human wild-type renin is known in the art; see, Imai, T.et al., Proc. Natl. Acad. Sci. USA 1983, 80, 7105-7409. It is noted thatthe fragment of the renin protein useful for the assay comprises aminoacid residues 67-406 of human renin (active Renin). To prepare activeRenin, a fragment longer than active renin (a preprorenin) (e.g.,comprising residues 1-406), may be expressed and from which a prorenin(e.g., comprising residues 23-406) may be recovered. The prorenin maylater be cleaved to obtain active Renin.

Expression of human preprorenin (residues 1-406) can be conducted usinga FreeStyle 293 Expression System (Invitrogen Corp.), wherein theplasmid DNA for human prorenin expression (pcDNA3.1(+)/hREN) is used toconduct transient expression in FreeStyle 293-F cells. Aftertransfection of the plasmid DNA, the cells are subjected to shaking at37° C., 8% CO₂ and 125 rpm for 3 days.

The prorenin protein is then accumulated and purified by salting out.Powdered ammonium sulfate is added to the culture medium and dissolvedto make a 40% saturation of the salt. The resulting precipitate can becollected by centrifugation and discarded. Ammonium sulfate is added tothe remaining solution and dissolved to make a 80% saturation of salt.The resulting precipitate can be collected by, for example,centrifugation. The prorenin protein is recovered by dissolving theprecipitate in buffer.

The concentrated liquid is subjected to gel filtration chromatographyusing, for example, HiLoad 16/60 Superdex 200 pg (Amersham Biosciences,Inc.) equilibrated with 20 mM Tris-hydrochloric acid (pH 8.0) containing0.15 M sodium chloride, at a flow rate of 1.4 mL/min, to obtain 3.6 mgof purified prorenin (residues 24-406).

Example B Purification of Active Renin

To 3.6 mg of prorenin (residues 24-406, as prepared in Example A)dissolved in 5.2 mL of 0.1 M Tris-hydrochloric acid (pH 8.0), is added12 μg of trypsin (Roche Diagnostics Corp.), and the mixture is allowedto react at 28° C. for 55 minutes to carry out activation of Renin.After the reaction, 0.4 mL of immobilized trypsin inhibitor (PierceBiotechnology, Inc.) is added to remove the trypsin used in theactivation, by adsorption. The reaction liquid containing the activerenin is concentrated using Vivaspin 20 (molecular weight of thefraction 10,000; Vivascience, Inc.), and diluted with 20 mMTris-hydrochloric acid (pH 8.0). The diluted liquid is fed to a TSKgelDEAE-5 PW column (7.5 mm I.D.×75 mm, Tosoh Corp.) equilibrated with 20mM Tris-hydrochloric acid (pH 8.0) at a flow rate of 1 mL/min to adsorbthe active renin (residues 67-406). The column is washed with the buffersolution used for the equilibration, and then elution is carried out bymeans of a linear concentration gradient of sodium chloride from 0 M to0.3 M, to obtain 1.5 mg of purified active renin (residues 67-406).

Example C Establishment of Renin Expressing Vector

A plasmid DNA to express human renin in HEK293 cells can be prepared asfollows. PCR is carried out using human renal cDNA (ClontechLaboratories, Inc., Marathon Ready cDNA) as the template and using twosynthetic DNAs (5′-AAGCTTATGGATGGATGGAGA-3′ (SEQ ID NO: 1) and5′-GGATCCTCAGCGGGCCAAGGC-3′ (SEQ ID NO: 2)), and the obtained fragmentis cloned using TOPO TA Cloning Kit (Invitrogen Corp.). The obtainedfragment is subcloned into pcDNA3.1(+) that has been cleaved by HindIIIand BamHI, to obtain a plasmid DNA for human preprorenin expression(pcDNA3.1(+)/hREN).

Example D Assaying the In Vitro Enzymatic Activity of Renin Inhibitors

Solutions of test compounds in varying concentrations (≦2 mM finalconcentration) are prepared in dimethyl sulfoxide (DMSO) and thendiluted into assay buffer comprising 50 mM Hepes, 1 mM EDTA, 1 mM DTT,0.1 mg/mL BSA, 0.01% Brij35, pH 7.4. Alternatively, the assay can beperformed with a high BSA concentration, wherein the buffer contains anadditional 2% BSA.

Recombinant human renin (3 nM final concentration) is added to thedilutions and pre-incubated with the compounds for 10 minutes at 37° C.As described in Examples A-C above, human renin can be obtained byexpressing preprorenin (residue 1-406) in mammalian cells, treating theprorenin (residues 24-406) contained in the culture supernatant withtrypsin, and isolate the active form (residues 67-406). Afterpre-incubation, the reaction is initiated with 1 μM of substrateQXL520-γ-Abu-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Thr-Lys(HiLyteFluo488)-Arg-OH (Anaspec, San Jose, Calif.). The final DMSO inthe assay is 5%. The total volume of the reaction mixture is 20 μL,which can be placed on Greiner 384-well small volume plates.

Renin activity may be determined via fluorescence (excitation λ=485 nm;emission λ=538 nm), e.g., on a Molecular Devices SPECTROmax GEMINI XPS.The fluorescence intensity is determined upon the addition of substrateand determined again after incubation at 37° C. for one hour. Thefluorescence intensity of a blank (no inhibition) using vehicle alone isalso determined. Renin activity is linearly proportional to the changein fluorescence observed (final−initial).

The percent inhibition of renin at a given compound concentration isdefined as:100%×[1−(F_(compound)/F_(blank))]where F_(compound) is the observed fluorescence at a given concentrationof test compound and F_(blank) is the observed fluorescence in thepresence of vehicle alone.

The pIC₅₀ value (negative log of the molar concentration of the compoundthat produces 50% inhibition) of a test compound is calculated bynon-linear least squares curve fitting of the equation:Percent Inhibition=100%/(1+(10^(−pIC50)/10^(log [I])))to percent inhibition versus compound concentration. The 50% inhibitoryconcentration (IC₅₀) of a test compound is calculated by raising 10 tothe negative pIC₅₀ (10^(−pIC50)).

IC₅₀ values for selected compounds of the present invention are given inTable 1.

TABLE 1 IC₅₀ of Exemplified Compounds Against Renin EXAMPLE IC₅₀ (nM) 13 >1,000  14 <100  17C  500-1,000  17D >1,000  17E 100-500  17F100-500  17H 100-500  17J 100-500  18 >1,000  19 >1,000  20 >1,000 21 >1,000  22  500-1,000  23 >1,000  24 >1,000  25 >1,000  26 >1,000 27 100-500  28 >1,000  29  500-1,000  32 >1,000  33 >1,000  34 >1,000 35  500-1,000  36 >1,000  37 >1,000  38 >1,000  39 >1,000  40 >1,000 41 >1,000  42 >1,000  43 >1,000  44 >1,000  45 100-500  46 >1,000 47 >1,000  48 >1,000  49 >1,000  50  500-1,000  51 100-500  52 100-500 53 >1,000  54 >1,000  55 100-500  56 100-500  57 >1,000  58 >1,000 59 >1,000  60 >1,000  61 >1,000  62 >1,000  63 >1,000  64 <100  65 <100 66 <100  67 100-500  68 >1,000  69 100-500  70 <100  71 100-500  72100-500  73 100-500  74 <100  75 <100  76 <100  77 <100  78 >1,000  79 500-1,000  80 >1,000  81 >1,000  82 >1,000  83 100-500  84 100-500 85 >1,000  86 100-500  87 100-500  88 <100  89 >1,000  90  500-1,000 91 100-500  92 >1,000  93 >1,000  94 >1,000  95 >1,000  96  500-1,000 97 >1,000  98  500-1,000  99 >1,000 100  500-1,000 101 >1,000 102100-500 103 100-500 104  500-1,000 105 >1,000 106 100-500 107  500-1,000108 <100 109 <100 110 <100 111 <100 112 <100 113 <100 114 <100 115 500-1,000 116 <100 117 <100 118 <100 119 <100 120 100-500 121 100-500122 <100 123 100-500 124 <100 125 <100 126 <100 127 100-500 128 <100 129<100 130 <100 131 <100 132 <100 133 >1,000 134  500-1,000 135 <100 136<100 137 <100 138 100-500 139 <100 140 <100 141 >1,000 142 100-500 143100-500 144  500-1,000 145 >1,000 146 100-500 147 >1,000 148 >1,000 149100-500 150 >1,000 151 100-500 152  500-1,000 153 >1,000 154 >1,000155 >1,000 156 >1,000 157 >1,000 158 >1,000 159 >1,000 160 >1,000 161100-500 162 100-500 163 >1,000 164  500-1,000 165 >1,000 166  500-1,000167 >1,000 168 100-500 169 >1,000 170 >1,000 171 >1,000 172 >1,000173 >1,000 174 >1,000 175 100-500 176 >1,000 177  500-1,000 178 >1,000179  500-1,000 180 100-500 181 >1,000 182 100-500 183 >1,000 184 >1,000185 >1,000 186 100-500 187 >1,000 188 100-500 189 >1,000 190  500-1,000191 100-500 192 >1,000 193 >1,000 194 <100 195  500-1,000 196 >1,000197 >1,000 198 100-500 199  500-1,000 200  500-1,000 202  500-1,000 203 500-1,000 204  500-1,000 205 >1,000 206  500-1,000 207 >1,000 208 500-1,000 209 >1,000 210 >1,000 211 100-500 212  500-1,000 213 100-500214  500-1,000 215 100-500 216 >1,000 217 <100 218 100-500 219 100-500220 <100 221 100-500 222 100-500 223  500-1,000 224 100-500 225 100-500226 100-500 227 >1,000 228  500-1,000 229  500-1,000 230 >1,000231 >1,000 232  500-1,000 233  500-1,000 234  500-1,000 235  500-1,000236 >1,000 237 >1,000 238 >1,000 239 >1,000 240 >1,000 241 >1,000242 >1,000 243 >1,000 244 >1,000 245 >1,000 246 >1,000 247 >1,000248 >1,000 249 >1,000 250 >1,000 251 >1,000 252 >1,000 253 >1,000254 >1,000 255 >1,000

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the compounds, compositions,kits, and methods of the present invention without departing from thespirit or scope of the invention. Thus, it is intended that the presentinvention cover the modifications and variations of this inventionprovided they come within the scope of the appended claims and theirequivalents.

What is claimed is:
 1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein C^(a) denotes acarbon atom; N^(a) denotes a nitrogen atom; R₁ is selected from

wherein m is 0, 1, 2, 3 or 4; l is 0, 1, 2 or 3; and each R₁₃ isselected from alkyl, halo, and alkoxy; R₂ is selected from methyl,isobutyl, —CH₂C(O)NH₂, —CH₂CH₂OCH₃, —CH₂CH₂═CH₂,

wherein R₄₀ is selected from H, fluoro, chloro, methyl, and methoxy; andR₄₁ is selected from isopropyl and isobutyl; R₃ is selected from

wherein R₂₄ is selected from hydrogen, alkyl, aryl, and heteroaryl; R₃₇is selected from hydrogen, (C₁₋₈)alkyl, (C₁₋₄)alkoxy(C₁₋₈)alkyl; and R₃₈is selected from (C₁₋₈)alkyl, (C₁₋₄)alkoxy(C₁₋₈)alkyl, and—(C₁₋₈)alkyl-NHC(O)(C₁₋₄)alkyl; R₄ is selected from hydrogen,(C₁₋₆)alkyl, —CH₂N(R₂₈)C(O)R₂₉, —(CH₂)_(n)OR₂₈,

wherein n is 1, 2, or 3; R₂₈ is hydrogen; and R₂₉ is phenyl.
 2. Thecompound according to claim 1, wherein R₁ is a fluoro or chlorosubstituted phenyl or benzyl.
 3. The compound according to claim 1,wherein R₁ is selected from the group consisting of isopropyl,cyclopropyl, and cyclopropylmethyl.
 4. The compound according to claim1, wherein R₂ is selected from methyl, —CH₂CH₂═CH₂,


5. The compound according to claim 1, wherein R₂ is selected fromisobutyl, —CH₂C(O)NH₂, —CH₂CH₂═CH₂,

wherein R₄₀ is selected from H, fluoro, chloro, methyl, and methoxy. 6.The compound according to claim 1, wherein R₂ is selected from—CH₂CH₂═CH₂,


7. The compound according to claim 1, wherein R₂ is selected frommethyl, —CH₂C(O)NH₂, —CH₂CH₂═CH₂,


8. The compound according to claim 1, wherein R₃ is selected from:


9. The compound according to claim 1, wherein R₃ is selected from:


10. The compound according to claim 1, wherein R₁ is phenyl; R₃ isselected from

and R₄ is selected from


11. A compound selected from:(S)-1-((2-Chloro-6-(3-hydroxypyrrolidin-1-yl)pyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;(R)-1-((2-Chloro-6-(3-hydroxypyrrolidin-1-yl)pyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-((2,6-bis((R)-3-Hydroxypyrrolidin-1-yl)pyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-((2,6-bis((S)-3-Hydroxypyrrolidin-1-yl)pyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-Cyclohexyl-3-((2,6-di(2methoxyl-pyridine-4-yl)pyridin-4-yl)methyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-Cyclohexyl-3-((6′-methoxy-2,3′-bipyridin-4-yl)methyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-((6-Chloro-6′-methoxy-2,3′-bipyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-Cyclohexyl-3-((6-(dimethylamino)-6′-methoxy-2,3′-bipyridin-4-yl)methyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-Cyclohexyl-3-((6-(diethylamino)-6′-methoxy-2,3′-bipyridin-4-yl)methyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1,5-Diphenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;5-Phenyl-4-(piperazine-1-carbonyl)-1-(pyridin-2-yl)-1H-imidazol-2(3H)-one;4-(2-(Hydroxymethyl)piperazine-1-carbonyl)-1,5-diphenyl-1H-imidazol-2(3H)-one;5-(3-Fluorophenyl)-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3-Morpholinophenyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;5-Isopropyl-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;5-Cyclopropyl-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;5-(Cyclopropylmethyl)-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;5-(2-Chlorophenyl)-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;5-(3-Chlorophenyl)-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;5-(4-Chlorophenyl)-1-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-Cyclohexyl-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;Benzyl3-(2-oxo-5-phenyl-4-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate;1-((1R,2R)-2-(Benzyloxy)cyclohexyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(2-(2-Methoxyethoxy)phenyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(2-(3-Methoxypropoxy)phenyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3-(2-Methoxyethoxy)phenyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3-(3-Methoxypropoxy)phenyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(6-(3-Methoxypropoxy)pyridin-2-yl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;(R)-1-Cyclohexyl-4-(3-methylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one;1-Cyclohexyl-4-(3-methylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one;(S)-1-Cyclohexyl-4-(3-methylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one;1-Cyclohexyl-4-(3,5-dimethylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one;1-Cyclohexyl-4-(2,5-dimethylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one;5-(3-Chlorophenyl)-1-(3-(3-methoxypropoxy)phenyl)-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;5-(3-Chlorophenyl)-1-(3-(2-methoxyethoxy)phenyl)-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(1H-Benzo[d]imidazol-2-yl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-Benzyl-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-Benzyl-4-phenyl-5-(piperazine-1-carbonyl)-3-(pyridin-2-yl)-1H-imidazol-2(3H)-one;1-((5-Methylisoxazol-3-yl)methyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-((5-Cyclopropyl-1,3,4-thiadiazol-2-yl)methyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-((1H-Imidazol-4-yl)methyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-((2-Aminothiazol-4-yl)methyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3-Fluorobenzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3,4-Difluorobenzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1,5-Diphenyl-4-(piperazine-1-carbonyl)-3-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-2(3H)-one;1-Methyl-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-3-methyl-1-(3-morpholinophenyl)-5-phenyl-1H-imidazol-2(3H)-one;1-Benzyl-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3-(Morpholine-4-carbonyl)benzyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3-Morpholinophenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-(3-(piperidine-1-carbonyl)benzyl)-1H-imidazol-2(3H)-one;2-(3-((3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)phenoxy)aceticacid;1-Cyclohexyl-3-methyl-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-Allyl-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;2-(3-Cyclohexyl-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)acetamide;(R)-1-Allyl-5-(2-benzylpiperazine-1-carbonyl)-3-cyclohexyl-4-phenyl-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-cyclohexyl-3-methyl-5-phenyl-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-cyclohexyl-3-(2-methoxyethyl)-5-phenyl-1H-imidazol-2(3H)-one;(R)-2-(5-(2-Benzylpiperazine-1-carbonyl)-3-cyclohexyl-2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)acetamide;Methyl2-(3-cyclohexyl-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)-2-phenylacetate;1-Cyclohexyl-5-phenyl-3-(1-phenylethyl)-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-cyclohexyl-3-methyl-5-phenyl-1H-imidazol-2(3H)-one;1-Cyclohexyl-3-phenethyl-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3-(1H-Pyrrol-1-yl)benzyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;(R)-2-(5-(2-Benzylpiperazine-1-carbonyl)-2-oxo-3,4-diphenyl-2,3-dihydro-1H-imidazol-1-yl)acetamide;1-(3-Morpholinophenyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3-(3-Methoxypropoxy)phenyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3-(Benzyloxy)benzyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3-(1H-Pyrrol-1-yl)benzyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;N-Isobutyl-N-methyl-3-((3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)benzamide;3-((2-oxo-3,4-Diphenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)benzonitrile;Methyl3-((2-oxo-3,4-Diphenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)benzoate;1-Benzyl-4-phenyl-5-(piperazine-1-carbonyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2(3H)-one;1,5-Diphenyl-4-(piperazine-1-carbonyl)-3-(quinolin-8-ylmethyl)-1H-imidazol-2(3H)one;1-(3-Methoxybenzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(Naphthalen-2-ylmethyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;2-((2-oxo-3,4-Diphenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)methyl)benzonitrile;1-(3,5-Dimethoxybenzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(4-Chloro-3-(trifluoromethoxy)benzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1Himidazol-2(3H)-one;1-(3-(1H-Pyrrol-1-yl)benzyl)-3,4-diphenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-((2-Chloro-6-morpholinopyridin-4-yl)methyl)-3-cyclohexyl-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-Cyclohexyl-3-((2,6-di(1H-pyrazol-4-yl)pyridin-4-yl)methyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(1-Acetylpiperidin-3-yl)-3-(3-methoxybenzyl)-5-phenyl-4-(piperazine-1carbonyl)-1H-imidazol-2(3H)-one;1-(1-Acetylpiperidin-3-yl)-3-benzyl-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(1-Acetylpiperidin-3-yl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(1-Benzoylpiperidin-3-yl)-3-benzyl-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-Benzyl-4-phenyl-3-(1-(phenylsulfonyl)piperidin-3-yl)-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-Benzyl-3-(1-(furan-2-carbonyl)piperidin-3-yl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;5-Phenyl-1-(1-(phenylsulfonyl)piperidin-3-yl)-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(1-Acetylpiperidin-3-yl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-Benzyl-4-phenyl-3-(1-(phenylsulfonyl)piperidin-3-yl)-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-Benzyl-4-phenyl-5-(piperazine-1-carbonyl)-3-(1-(pyridin-2-ylsulfonyl)piperidin-3-yl)-1H-imidazol-2(3H)-one;1-(3-Phenoxybenzyl)-4-phenyl-3-(1-(phenylsulfonyl)piperidin-3-yl)-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3-Phenoxybenzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-(1-(pyridin-2-ylsulfonyl)piperidin-3-yl)-1H-imidazol-2(3H)-one;1-(1-Acetylpiperidin-3-yl)-4-((R)-2-benzylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one;1-Benzyl-3-((1R,2R)-2-hydroxycyclohexyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-((1R,2R)-2-Hydroxycyclohexyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;N—(((S)-1-(1-((1R,2R)-2-Hydroxycyclohexyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazin-2-yl)methyl)benzamide;(S)—N-((1-(1-Cyclohexyl-2-oxo-5-phenyl-2,3-dihydro-1H-imidazole-4-carbonyl)piperazin-2-yl)methyl)benzamide;(R)-4-(2-Benzylpiperazine-1-carbonyl)-1,5-diphenyl-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(3-morpholinophenyl)-5-phenyl-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-cyclohexyl-5-phenyl-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(2,3-dimethoxyphenyl)-5-phenyl-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(2-methoxyphenyl)-5-phenyl-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(3-(methylsulfonyl)phenyl)-5-phenyl-1H-imidazol-2(3H)-one;1-(1-Acetylpiperidin-3-yl)-4-((R)-2-benzylpiperazine-1-carbonyl)-5-phenyl-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-5-phenyl-1-o-tolyl-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(2-nitrophenyl)-5-phenyl-1H-imidazol-2(3H)-one;(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)methanesulfonamide;(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)propane-1-sulfonamide;(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)cyclopropanecarboxamide;(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)butyramide;(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)acetamide;(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)cyclopropanesulfonamide;(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)benzamide;(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)Benzenesulfonamide;4-((R)-2-Benzylpiperazine-1-carbonyl)-1-((1S,2S)-2-hydroxycyclohexyl)-5-phenyl-1H-imidazol-2(3H)-one;(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)ethanesulfonamide;(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)butane-1-sulfonamide;(R)—N-(2-(4-(2-Benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)phenyl)prop-2-ene-1-sulfonamide;(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-((1-hydroxycyclohexyl)methyl)-5-phenyl-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-5-phenyl-1-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-5-phenyl-1-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(1-butyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-cyclopropyl-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-5-cyclopropyl-1-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-phenyl-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(indolin-6-yl)-5-phenyl-1H-imidazol-2(3H)-one;(R)-4-(2-Benzylpiperazine-1-carbonyl)-1-(4-(2-methoxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-phenyl-1H-imidazol-2(3H)-one;4-((R)-2-Benzylpiperazine-1-carbonyl)-1-(3-methoxy-2,3-dihydro-1H-inden-5-yl)-5-phenyl-1H-imidazol-2(3H)-one;(R)-4-(2-(2-Phenoxyethyl)piperazine-1-carbonyl)-5-phenyl-1-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-imidazol-2(3H)-one;1-Allyl-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one;1-(3-Phenoxybenzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one;1-(3-Methoxybenzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one;1-(3,4-Difluorobenzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one;1-Allyl-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(2-Methoxyphenyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3-Methoxybenzyl)-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3,4-Difluorobenzyl)-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3-(2-Phenoxyethoxy)benzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one;1-Allyl-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3-Methoxybenzyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-((1S,2R)-2-Hydroxycyclohexyl)-3-(3-phenoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-((1S,2R)-2-Hydroxycyclohexyl)-3-(3-methoxybenzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3,4-Difluorobenzyl)-3-((1S,2R)-2-hydroxycyclohexyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;N-(2-(2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;N-(3-(2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;1-(Cyclohexylmethyl)-3-((1S,2R)-2-hydroxycyclohexyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;N-(2-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;N-(3-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;1-(Cyclohexylmethyl)-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;N-(3-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;N-(3-(2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;1-(Cyclohexylmethyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one;1-(3,4-Difluorobenzyl)-3-(3-(3-methoxypropoxy)phenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;3-Methyl-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)butanamide;N-(2-(2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;N-(3-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)-3-methylbutanamide;N-(2-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;N-(2-(3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)-3-methylbutanamide;N-(3-(3-((2S)-2-Hydroxycyclohexyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;N-(3-(3-((2S)-2-Hydroxycyclohexyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;N-(3-(3-((2S)-2-Hydroxycyclohexyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)-3-methylbutanamide;N-(2-(3-((2S)-2-Hydroxycyclohexyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)-3-methylbutanamide;N-(3-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazolidin-1-yl)propyl)benzamide;N-(3-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;3-Methyl-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)butanamide;N-(2-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;3-Methyl-N-(2-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)butanamide;N-(3-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;N-(3-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;N-(3-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)-3-methylbutanamide;N-(2-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;N-(2-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;N-(2-(3-(3-(3-Methoxypropoxy)phenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)-3-methylbutanamide;N-(2-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;1-(3-(2-Methoxyethoxy)benzyl)-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-1H-imidazol-2(3H)-one;1-(3-(2-Methoxyethoxy)benzyl)-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(2-Methoxyphenyl)-3-(3-(2-phenoxyethoxy)benzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(Cyclohexylmethyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3,4-Difluorobenzyl)-3-(3-morpholinophenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3-Morpholinophenyl)-3-(3-(2-phenoxyethoxy)benzyl)-5-phenyl-4-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;1-(3-(2-Methoxyethoxy)benzyl)-3-(3-(3-methoxypropoxy)phenyl)-4-phenyl-5-(piperazine-1-carbonyl)-1H-imidazol-2(3H)-one;2-Fluoro-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;2-Chloro-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;3-Chloro-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;N-(3-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)propane-2-sulfonamide;2-Methyl-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;3-Methoxy-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;4-Methoxy-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;1-(3-(3-(3-Morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)-3-phenylurea;1-Isopropyl-3-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)urea;4-Chloro-N-(3-(3-(3-morpholinophenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;2-Fluoro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;2-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;3-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;4-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)propane-2-sulfonamide;2-Methyl-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;3-Methoxy-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;4-Methoxy-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzenesulfonamide;1-(2-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)-3-phenylurea;1-(2-Chlorophenyl)-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea;1-(4-Chlorophenyl)-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea;1-(2-Methoxyphenyl)-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea;1-(3-Methoxyphenyl)-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea;1-Isopropyl-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea;2-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;3-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;4-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;2-Methyl-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;3-Methoxy-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;4-Methoxy-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;1-(3-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)-3-phenylurea;1-(2-Chlorophenyl)-3-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)urea;1-(2-Methoxyphenyl)-3-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)urea;1-(3-Methoxyphenyl)-3-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)urea;1-Isopropyl-3-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)urea;1-(4-Methoxyphenyl)-3-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)urea;2-Fluoro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzenesulfonamide;2-Fluoro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;2-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;2-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;3-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;4-Chloro-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;2-Methoxy-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;4-Methoxy-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)benzamide;N-(2-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)isobutyramide;N-(2-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)cyclohexanecarboxamide3-Methyl-N-(2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethyl)butanamide;N-(3-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)propane-2-sulfonamide;2-Fluoro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;2-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;3-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;4-Chloro-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;2-Methoxy-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;4-Methoxy-N-(3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)benzamide;N-(3-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)isobutyramide;N-(3-(2-Oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propyl)cyclohexanecarboxamide;Phenyl2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethylcarbamate;Methyl2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethylcarbamate;Ethyl2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethylcarbamate;Benzyl2-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)ethylcarbamate;Phenyl3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propylcarbamate;Methyl3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propylcarbamate;Ethyl3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propylcarbamate;Benzyl3-(2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-o-tolyl-2,3-dihydro-1H-imidazol-1-yl)propylcarbamate;1-(2-Methylphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-2-one;1-(Cyclohexylmethyl)-3-(2-methylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-(2-Methylphenyl)-3-[(3-phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[(2-Amino1,3-thiazol-4-yl)methyl]-3-(2-methylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-[(3-Methoxyphenyl)methyl]-3-(2-methylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-[(3,4-Difluorophenyl)methyl]-3-(2-methylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;N-[2-[3-(2-Methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzamide;N-[2-[3-(2-Methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzenesulfonamide;3-Methyl-N-[2-[3-(2-methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]butanamide;2-Methyl-N-[2-[3-(2-methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]propane-1-sulfonamide;N-[3-[3-(2-Methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzamide;N-[3-[3-(2-Methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzenesulfonamide;3-Methyl-N-[3-[3-(2-methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]butanamide;2-Methyl-N-[3-[3-(2-methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]propane-1-sulfonamide;1-[[3-(2-Methoxyethoxy)phenyl]methyl]-3-(2-methylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-(2-Methylphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-2-one;1-(2-Methylphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-2-one;1-(2-Methylphenyl)-3-[[3-(2-phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-(2-Methylphenyl)-3-[[3-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-(2-Methylphenyl)-3-[[3-[2-oxo-2-(1-piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;N-Methyl-2-[3-[[3-(2-methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]acetamide;2-[3-[[3-(2-Methylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;1-(2-Methoxyphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-2-one;1-(Cyclohexylmethyl)-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-(2-Methoxyphenyl)-3-[(3-phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[(2-Amino1,3-thiazol-4-yl)methyl]-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-(2-Methoxyphenyl)-3-[(3-methoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[(3,4-Difluorophenyl)methyl]-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;N-[2-[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzamide;N-[2-[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzenesulfonamide;N-[2-[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-3-methyl-butanamide;N-[2-[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-2-methyl-propane-1-sulfonamide;N-[3-[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzamide;N-[3-[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzenesulfonamide;N-[3-[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-3-methyl-butanamide;N-[3-[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-2-methyl-propane-1-sulfonamide;1-[[3-(2-Methoxyethoxy)phenyl]methyl]-3-(2-methoxyphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-(2-Methoxyphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-2-one;1-(2-Methoxyphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-2-one;1-(2-Methoxyphenyl)-3-[[3-(2-phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-(2-Methoxyphenyl)-3-[[3-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-(2-Methoxyphenyl)-3-[[3-[2-oxo-2-(1-piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;2-[3-[[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-methyl-acetamide;2-[3-[[3-(2-Methoxyphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;1-(3-Morpholin-4-ylphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-2-one;1-(Cyclohexylmethyl)-3-(3-morpholin-4-ylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-(3-Morpholin-4-ylphenyl)-3-[(3-phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[(2-Amino1,3-thiazol-4-yl)methyl]-3-(3-morpholin-4-ylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-[(3-Methoxyphenyl)methyl]-3-(3-morpholin-4-ylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-[(3,4-Difluorophenyl)methyl]-3-(3-morpholin-4-ylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;N-[2-[3-(3-Morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzamide;N-[2-[3-(3-Morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzenesulfonamide;3-Methyl-N-[2-[3-(3-morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]butanamide;2-Methyl-N-[2-[3-(3-morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]propane-1-sulfonamide;N-[3-[3-(3-Morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzamide;N-[3-[3-(3-Morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzenesulfonamide;3-Methyl-N-[3-[3-(3-morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]butanamide;2-Methyl-N-[3-[3-(3-morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]propane-1-sulfonamide;1-[[3-(2-Methoxyethoxy)phenyl]methyl]-3-(3-morpholin-4-ylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-(3-Morpholin-4-ylphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-2-one;1-(3-Morpholin-4-ylphenyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-2-one1-(3-Morpholin-4-ylphenyl)-3-[[3-(2-phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[[3-(2-Morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-3-(3-morpholin-4-ylphenyl)-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-(3-Morpholin-4-ylphenyl)-3-[[3-[2-oxo-2-(1-piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;N-Methyl-2-[3-[[3-(3-morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]acetamide;2-[3-[[3-(3-Morpholin-4-ylphenyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;1-[3-(3-Methoxypropoxy)phenyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-2-one;1-(Cyclohexylmethyl)-3-[3-(3-methoxypropoxy)phenyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-[3-(3-Methoxypropoxy)phenyl]-3-[(3-phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[(2-Amino1,3-thiazol-4-yl)methyl]-3-[3-(3-methoxypropoxy)phenyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-[(3-Methoxyphenyl)methyl]-3-[3-(3-methoxypropoxy)phenyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-[(3,4-Difluorophenyl)methyl]-3-[3-(3-methoxypropoxy)phenyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;N-[2-[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzamide;N-[2-[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzenesulfonamide;N-[2-[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-3-methyl-butanamide;N-[2-[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-2-methyl-propane-1-sulfonamide;N-[3-[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzamide;N-[3-[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzenesulfonamide;N-[3-[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-3-methyl-butanamide;N-[3-[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-2-methyl-propane-1-sulfonamide;1-[[3-(2-Methoxyethoxy)phenyl]methyl]-3-[3-(3-methoxypropoxy)phenyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-[3-(3-Methoxypropoxy)phenyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-2-one;1-[3-(3-Methoxypropoxy)phenyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-2-one;1-[3-(3-Methoxypropoxy)phenyl]-3-[[3-(2-phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[3-(3-Methoxypropoxy)phenyl]-3-[[3-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[3-(3-Methoxypropoxy)phenyl]-3-[[3-[2-oxo-2-(1-piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;2-[3-[[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-methyl-acetamide;2-[3-[[3-[3-(3-Methoxypropoxy)phenyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;N-[(1S)-2-[2-oxo-5-Phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-1-yl]cyclohexyl]propanamide;N-[(1S)-2-[3-(Cyclohexylmethyl)-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;N-[(1S)-2-[2-oxo-3-[(3-Phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;N-[(1S)-2-[3-[(2-Amino1,3-thiazol-4-yl)methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;N-[(1S)-2-[3-[(3-Methoxyphenyl)methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;N-[(1S)-2-[3-[(3,4-Difluorophenyl)methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;N-[2-[2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-[(2S)-2-(propanoylamino)cyclohexyl]imidazol-1-yl]ethyl]benzamide;N-[(1S)-2-[3-[2-(Benzenesulfonamido)ethyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;3-Methyl-N-[2-[2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-[(2S)-2-(propanoylamino)cyclohexyl]imidazol-1-yl]ethyl]butanamide;N-[(1S)-2-[3-[2-(2-Methylpropylsulfonylamino)ethyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;N-[3-[2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-[(2S)-2-(propanoylamino)cyclohexyl]imidazol-1-yl]propyl]benzamide;N-[(1S)-2-[3-[3-(Benzenesulfonamido)propyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;3-Methyl-N-[3-[2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-[(2S)-2-(propanoylamino)cyclohexyl]imidazol-1-yl]propyl]butanamide;N-[(1S)-2-[3-[3-(2-Methylpropylsulfonylamino)propyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;N-[(1S)-2-[3-[[3-(2-Methoxyethoxy)phenyl]methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;N-[(1S)-2-[2-oxo-5-Phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-1-yl]cyclohexyl]propanamide;N-[(1S)-2-[2-oxo-5-Phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-1-yl]cyclohexyl]propanamide;N-[(1S)-2-[2-oxo-3-[[3-(2-Phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;N-[(1S)-2-[3-[[3-(2-Morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;N-[(1S)-2-[2-oxo-3-[[3-[2-oxo-2-(1-Piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;N-[(1S)-2-[3-[[3-(Methylcarbamoylmethoxy)phenyl]methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]cyclohexyl]propanamide;N-[(1S)-2-[2-oxo-5-Phenyl-4-(piperazine-1-carbonyl)-3-[[3-(propan-2-ylcarbamoylmethoxy)phenyl]methyl]imidazol-1-yl]cyclohexyl]propanamide;1-(1-Acetyl-3-piperidyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-2-one;1-(1-Acetyl-3-piperidyl)-3-(cyclohexylmethyl)-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-(1-Acetyl-3-piperidyl)-3-[(3-phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-(1-Acetyl-3-piperidyl)-3-[(2-amino1,3-thiazol-4-yl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-(1-Acetyl-3-piperidyl)-3-[(3-methoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-(1-Acetyl-3-piperidyl)-3-[(3,4-difluorophenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;N-[2-[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzamide;N-[2-[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzenesulfonamide;N-[2-[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-3-methyl-butanamide;N-[2-[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-2-methyl-propane-1-sulfonamide;N-[3-[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzamide;N-[3-[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzenesulfonamide;N-[3-[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-3-methyl-butanamide;N-[3-[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-2-methyl-propane-1-sulfonamide;1-(1-Acetyl-3-piperidyl)-3-[[3-(2-methoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-(1-Acetyl-3-piperidyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-2-one;1-(1-Acetyl-3-piperidyl)-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-2-one;1-(1-Acetyl-3-piperidyl)-3-[[3-(2-phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-(1-Acetyl-3-piperidyl)-3-[[3-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-(1-Acetyl-3-piperidyl)-3-[[3-[2-oxo-2-(1-piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;2-[3-[[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-methyl-acetamide;2-[3-[[3-(1-Acetyl-3-piperidyl)-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;1-[1-(Benzenesulfonyl)-3-piperidyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-2-one;1-[1-(Benzenesulfonyl)-3-piperidyl]-3-(cyclohexylmethyl)-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[1-(Benzenesulfonyl)-3-piperidyl]-3-[(3-phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[(2-Amino1,3-thiazol-4-yl)methyl]-3-[1-(benzenesulfonyl)-3-piperidyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-[1-(Benzenesulfonyl)-3-piperidyl]-3-[(3-methoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[1-(Benzenesulfonyl)-3-piperidyl]-3-[(3,4-difluorophenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;N-[2-[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzamide;N-[2-[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzenesulfonamide;N-[2-[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-3-methyl-butanamide;N-[2-[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-2-methyl-propane-1-sulfonamide;N-[3-[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzamide;N-[3-[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzenesulfonamide;N-[3-[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-3-methyl-butanamide;N-[3-[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-2-methyl-propane-1-sulfonamide;1-[1-(Benzenesulfonyl)-3-piperidyl]-3-[[3-(2-methoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[1-(Benzenesulfonyl)-3-piperidyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-2-one;1-[1-(Benzenesulfonyl)-3-piperidyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-2-one;1-[1-(Benzenesulfonyl)-3-piperidyl]-3-[[3-(2-phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[1-(Benzenesulfonyl)-3-piperidyl]-3-[[3-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[1-(Benzenesulfonyl)-3-piperidyl]-3-[[3-[2-oxo-2-(1-piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;2-[3-[[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-methyl-acetamide;2-[3-[[3-[1-(Benzenesulfonyl)-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;N-[2-[2-oxo-5-Phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-1-yl]phenyl]propane-1-sulfonamide;N-[2-[3-(Cyclohexylmethyl)-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;N-[2-[2-oxo-3-[(3-Phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;N-[2-[3-[(2-Amino1,3-thiazol-4-yl)methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;N-[2-[3-[(3-Methoxyphenyl)methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;N-[2-[3-[(3,4-Difluorophenyl)methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;N-[2-[2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]ethyl]benzamide;N-[2-[2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]ethyl]benzenesulfonamide;3-Methyl-N-[2-[2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]ethyl]butanamide;2-Methyl-N-[2-[2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]ethyl]propane-1-sulfonamide;N-[3-[2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]propyl]benzamide;N-[3-[2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]propyl]benzenesulfonamide;3-Methyl-N-[3-[2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]propyl]butanamide;2-Methyl-N-[3-[2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]propyl]propane-1-sulfonamide;N-[2-[3-[[3-(2-Methoxyethoxy)phenyl]methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;N-[2-[2-oxo-5-Phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-1-yl]phenyl]propane-1-sulfonamide;N-[2-[2-oxo-5-Phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-1-yl]phenyl]propane-1-sulfonamide;N-[2-[2-oxo-3-[[3-(2-Phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;N-[2-[3-[[3-(2-Morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-2-oxo-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;N-[2-[2-oxo-3-[[3-[2-oxo-2-(1-Piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-1-yl]phenyl]propane-1-sulfonamide;N-Methyl-2-[3-[[2-oxo-4-phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]methyl]phenoxy]acetamide;2-[3-[[2-oxo-4-Phenyl-5-(piperazine-1-carbonyl)-3-[2-(propylsulfonylamino)phenyl]imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;1-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-2-one;1-(Cyclohexylmethyl)-3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-3-[(3-phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[(2-Amino1,3-thiazol-4-yl)methyl]-3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-[(3-Methoxyphenyl)methyl]-3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-[(3,4-Difluorophenyl)methyl]-3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;N-[2-[3-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzamide;N-[2-[3-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzenesulfonamide;3-Methyl-N-[2-[3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]butanamide;2-Methyl-N-[2-[3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]propane-1-sulfonamide;N-[3-[3-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzamide;N-[3-[3-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzenesulfonamide;3-Methyl-N-[3-[3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]butanamide;2-Methyl-N-[3-[3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]propane-1-sulfonamide;1-[[3-(2-Methoxyethoxy)phenyl]methyl]-3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-2-one;1-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-2-one;1-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-3-[[3-(2-phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-3-[[3-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-3-[[3-[2-oxo-2-(1-piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;N-Methyl-2-[3-[[3-[1-(1-methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]acetamide;2-[3-[[3-[1-(1-Methylpyrazol-4-yl)sulfonyl-3-piperidyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;1-[(2R)-2-Hydroxycyclohexyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-prop-2-enyl-imidazol-2-one;1-(Cyclohexylmethyl)-3-[(2R)-2-hydroxycyclohexyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-[(2R)-2-Hydroxycyclohexyl]-3-[(3-phenoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[(2-Amino1,3-thiazol-4-yl)methyl]-3-[(2R)-2-hydroxycyclohexyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;1-[(2R)-2-Hydroxycyclohexyl]-3-[(3-methoxyphenyl)methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[(3,4-Difluorophenyl)methyl]-3-[(2R)-2-hydroxycyclohexyl]-4-phenyl-5-(piperazine-1-carbonyl)imidazol-2-one;N-[2-[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzamide;N-[2-[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]benzenesulfonamide;N-[2-[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-3-methyl-butanamide;N-[2-[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]ethyl]-2-methyl-propane-1-sulfonamide;N-[3-[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzamide;N-[3-[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]benzenesulfonamide;N-[3-[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-3-methyl-butanamide;N-[3-[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]propyl]-2-methyl-propane-1-sulfonamide;1-[(2R)-2-Hydroxycyclohexyl]-3-[[3-(2-methoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[(2R)-2-Hydroxycyclohexyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-pyridin-3-yloxyethoxy)phenyl]methyl]imidazol-2-one;1-[(2R)-2-Hydroxycyclohexyl]-5-phenyl-4-(piperazine-1-carbonyl)-3-[[3-(2-propan-2-yloxyethoxy)phenyl]methyl]imidazol-2-one;1-[(2R)-2-Hydroxycyclohexyl]-3-[[3-(2-phenoxyethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[(2R)-2-Hydroxycyclohexyl]-3-[[3-(2-morpholin-4-yl-2-oxo-ethoxy)phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;1-[(2R)-2-Hydroxycyclohexyl]-3-[[3-[2-oxo-2-(1-piperidyl)ethoxy]phenyl]methyl]-5-phenyl-4-(piperazine-1-carbonyl)imidazol-2-one;2-[3-[[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-methyl-acetamide;2-[3-[[3-[(2R)-2-Hydroxycyclohexyl]-2-oxo-4-phenyl-5-(piperazine-1-carbonyl)imidazol-1-yl]methyl]phenoxy]-N-propan-2-yl-acetamide;(R)-Ethyl6-(4-(2-benzylpiperazine-1-carbonyl)-2-oxo-5-phenyl-2,3-dihydro-1H-imidazol-1-yl)indoline-1-carboxylate;and a pharmaceutically acceptable salt of any one of the aforementionedcompounds.
 12. A pharmaceutical composition comprising a compound asdefined in claim 1 and a pharmaceutically acceptable excipient.
 13. Amethod of treating a disease in a subject, the method comprisingadministering a compound as defined in claim 1 to the subject having thedisease, wherein the disease is hypertension.